Eif4e-inhibiting compounds and methods

ABSTRACT

The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.For Formula I compounds X1, X2, X3, X4, X5, X6, Q, L1, L2, Y, R1, R2, R3, R4, R5, R6, R7, R8 and rings A, B and C are as defined in the specification. The inventive Formula I compounds are inhibitors of eIF4e and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/916,820, filed on Jun. 30, 2020, which claims the benefit of priorityto U.S. Provisional Patent Application No. 62/869,662, filed on Jul. 2,2019, the entire contents of which are herein incorporated by reference.

FIELD

The present invention generally relates to compounds having activity asinhibitors of eukaryotic initiation factor 4e (eIF4e), as well as torelated compositions and methods for utilizing the inventive compoundsas therapeutic agents for treatment of eIF4e dependent diseases,including the treatment of cancer.

BACKGROUND

Eukaryotic initiation factor 4E (eIF4E) is a general translation factor,but it has the potential to enhance preferentially the translation ofmessenger RNAs (mRNAs) that lead to production of malignancy-associatedproteins. This selectivity may relate to an increased requirement foreIF4E and its binding partners for the translation of mRNAs containingextensive secondary structure in their 5′-untranslated regions(5′-UTRs). These mRNAs include those encoding certain proteins thatcontrol cell cycle progression and tumorigenesis. Under normal cellularconditions the translation of these malignancy-associated mRNAs issuppressed as the availability of active eIF4E is limited; however,their levels can increase when eIF4E is over-expressed orhyperactivated. Elevated levels of eIF4E have been found in many typesof tumors and cancer cell lines including cancers of the colon, breast,bladder, lung, prostate, gastrointestinal tract, head and neck,Hodgkin's lymphomas and neuroblastomas.

Initiation of cap-dependent translation is thought to depend on theassembly of eIF4F, an initiation factor complex including eIF4E, thescaffold protein eIF4G, and the RNA helicase eIF4A. Because eIF4E is theonly one of these proteins that binds directly to the mRNA capstructure, it is the key factor for the assembly of eIF4F at the 5′ cap.The scaffold protein, eIF4G, also recruits the 40S ribosomal subunit tothe mRNA via its interaction with eIF3 and binds eIF4B, a protein thataids the RNA-helicase function of eIF4A, thus facilitating thetranslation of mRNAs that contain structured 5′-UTRs. The availabilityof eIF4E as part of the eIF4F complex is a limiting factor incontrolling the rate of translation, and therefore eIF4E is an importantregulator of mRNA translation.

Regulation of eIF4E activity forms a node of convergence of thePI3K/Akt/mTOR and Ras/Raf/MAPK signaling pathways. The PI3K(phosphoinositide 3-kinase)/PTEN (phosphatase and tensin homologuedeleted on chromosome ten)/Akt/mTOR (mammalian target of rapamycin)pathway is often involved in tumorigenesis and in sensitivity andresistance to cancer therapy. Deregulated signaling through thePI3K/PTEN/Akt/mTOR pathway is often the result of genetic alterations incritical components of this pathway and/or mutations at upstream growthfactor receptors or signaling components. PI3K initiates a cascade ofevents when activated by, for example, extracellular growth factors,mitogens, cytokines and/or receptors, PDK1 activates Akt, which in turnphosphorylates and inactivates the tumor suppressor complex comprisingTSC1 and 2 (tuberous sclerosis complex 1/2), resulting in the activationof mTORC1 (target of rapamycin complex 1) by Rheb-GTP. Activation ofPDK1 and Akt by PI3Ks is negatively regulated by PTEN.

PTEN is a critical tumor suppressor gene and is often mutated orsilenced in human cancers. Its loss results in activation of Akt andincreases downstream mTORC1 signaling. The involvement of mTOR complex1(mTORC1) in neoplastic transformation appears to depend on itsregulatory role toward the eIF4F complex; overexpression of eIF4E canconfer resistance to rapamycin. mTORC1 regulates the eIF4F complexassembly that is critical for the translation of mRNAs associated withcell growth, prevention of apoptosis and transformation. mTORC1 achievesthis by phosphorylation and inactivation of 4E-BPs and the subsequentdissociation of 4E-BPs from eIF4E. This then enables eIF4E to interactwith the scaffold protein eIF4G, permitting assembly of the eIF4Fcomplex for the translation of structured mRNAs. mTORC1 also promotesactivation of the translational activator, S6K, which phosphorylates theribosomal protein S6 and other substrates, including eIF4B. mTORC1signaling is inhibited by rapamycin and its analogues (rapalogs),although these compounds act allosterically, rather than directlyinhibiting mTOR kinase activity.

Given the importance of the PI3K/Akt/mTOR pathway in regulating mRNAtranslation of genes that encode for pro-oncogenic proteins andactivated mTORC1 signaling in a high proportion of cancers, thesekinases have been actively pursued as oncology drug targets. A number ofpharmacological inhibitors have been identified, some of which havereached advanced clinical stages. However, it has recently become clearthat the mTOR pathway participates in a complicated feedback loop thatcan impair activation of Akt. It has been shown that prolonged treatmentof cancer cells or patients with mTOR inhibitors causes elevated PI3Kactivity that leads to phosphorylation of Akt and eIF4E, and promotescancer cell survival. eIF4E, acting downstream of Akt and mTOR,recapitulates Akt's action in tumorigenesis and drug resistance, and Aktsignaling via eIF4E is an important mechanism of oncogenesis and drugresistance in vivo.

In addition to the PI3K/Akt/mTOR pathway, eIF4E is also the target ofthe Ras/Raf/MAP signaling cascade which is activated by growth factorsand for the stress-activated p38 MAP kinase pathway. Erk1/2 and p38 thenphosphorylate MAP kinase-interacting kinase 1 (Mnk1) and MAPkinase-interacting kinase 2 (Mnk2). The Erk pathway is also activated inmany cancers, reflecting, for example, activating mutations in Ras(found in around 20% of tumors) or loss of function of the RasGTPase-activator protein NF1. Mnk1 and Mnk2 are threonine/serine proteinkinases and specifically phosphorylate serine 209 (Ser209) of eIF4Ewithin the eIF4F complex, by virtue of the interaction between eIF4E andthe Mnks, which serves to recruit Mnks to act on eIF4E. Mice withmutated eIF4E, in which Ser209 is replaced by alanine, show no eIF4Ephosphorylation and significantly attenuated tumor growth.Significantly, while Mnk activity is necessary for eIF4E-mediatedoncogenic transformation, it is dispensable for normal development.Pharmacologically inhibiting Mnks thus presents an attractivetherapeutic strategy for cancer.

Despite increased understanding of Mnk structure and function, littleprogress has been made with regard to the discovery of pharmacologicalMnk inhibitors and relatively few Mnk inhibitors have been reported:CGP052088 (Tschopp et al., Mol Cell Biol Res Commun. 3(4):205-211,2000); CGP57380 (Rowlett et al., Am J Physiol Gastrointest LiverPhysiol. 294(2):G452-459, 2008); and Cercosporamide (Konicek et al.,Cancer Res. 71(5):1849-1857, 2011). These compounds, however, havemainly been used for the purpose of Mnk target validation. Morerecently, investigators have proposed further compounds for treatingdiseases influenced by the inhibition of kinase activity of Mnk1 and/orMnk2, including, for example, the compounds disclosed in InternationalPatent Application Publication WO 2014/044691 and the various patentdocuments cited therein, the4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3-d]pyrimidinesdisclosed by Yu et al., European Journal of Med. Chem., 95: 116-126,2015, and the6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dioneand the various compounds disclosed in International Patent ApplicationPublication WO 2015/200481.

Accordingly, while advances have been made in this field there remains asignificant need in the art for compounds that specifically inhibiteFI4E activity, particularly with regard to eIF4E's role in regulationof cancer pathways, as well as for associated composition and methods.The present invention fulfils this need and provides further relatedadvantages.

SUMMARY

The present invention is directed to compounds that inhibit or modulatethe activity of eIF4E, as well as stereoisomers, tautomers andpharmaceutically acceptable salts of such compounds. The presentinvention also is directed to pharmaceutically acceptable compositionscontaining such compounds and associated methods for treating conditionsthat would benefit from eIF4E inhibition, such as cancer.

In one embodiment the invention is directed to compounds according toFormula I

or stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein:

X¹ is CR², —C-L¹-Y or N;

X², X⁵ and X⁶ are independently CR² or N,

-   -   wherein X⁵ and X⁶ together with 3 or 4 carbon or nitrogen atoms        combine to form a 5- or 6-membered cycloalkyl or heterocyclyl,    -   or when X² is CR², R¹ and R² together with the atoms they        attached to form a 6-membered aryl or heteroaryl;

X³ is C, or X³ is C or N when X⁴ is a bond;

X⁴ is a bond, CR² or N,

-   -   wherein X⁴ and X⁵ together with 3 or 4 carbon or nitrogen atoms        combine to form a 5- or 6-membered heteroaryl;

Q is H or -L¹-Y;

L¹ is —(CH₂)—, —(CH₂)₂—, —(CH₂)₃—, —CH((C₁-C₈)alkyl)(CH₂)—,—CH((C₁-C₈)alkyl)(CH₂)₂—, —(CH₂)₂—O—, —CH₂CH═CH—, —CH₂C≡C— or—CH₂(cyclopropyl)-;

Y is

wherein

Ring B is a six-membered aryl, heteroaryl or heterocyclyl;

R¹ is H, OH, halo, CN, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₆)cycloalkylor NR⁵R⁵;

R² is independently H, halo, CN, NO, NO₂, C≡H, (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, CH₂SR⁵, OR⁵, NHR⁵, NR⁵R⁵,[(C₁-C₈)alkylene]heterocyclyl, [(C₁-C₈)alkylene]heteroaryl,[(C₁-C₈)alkylene]NHR⁵, [(C₁-C₈)alkylene]NR⁵R⁵, [(C₁-C₈)alkylyne]NR⁵R⁵,C(O)R⁵, C(O)OR⁵, C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO₂R⁵, SO₂NHR⁵,SO₂NR⁵R⁵, NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl orheterocyclyl;

R³ is independently OH, halo, CN, NO₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₁-C₆)alkoxy, C≡H, NHR⁷, NR⁷R⁷, CO₂H, CO₂R⁷, [(C₁-C₃)alkylene](C₁-C₃)alkoxy, [(C₁-C₃)alkylene]CO₂H, (C₃-C₈)cycloalkyl, ═O. ═S, SR⁷,SO₂R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁴ is H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy,SR⁷ or Z, wherein Z is

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

L² is —C(R⁶)(R⁶)—, —C(R⁶)(R⁶)C(R⁶)(R⁶)—, —C(R⁶)═C(R⁶)—,—N(R⁵)C(R⁶)(R⁶)—, —OC(R⁶)(R⁶)—, —C(═O)—, —C(═O)N(R⁵)C(R⁶)(R⁶)— or abond;

R⁵ is independently H, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₃-C₅)cycloalkyl, CO₂H, [(C₁-C₃)alkylene]heteroaryl,[(C₁-C₃)alkylene]aryl, [(C₁-C₃)alkylene]CO₂H, heterocyclyl, aryl orheteroaryl,

or wherein two R⁵ substituents together with a nitrogen atom form a 4-,5-, 6- or 7-membered heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy, NHR⁷, NR⁷R⁷, CO₂H, [(C₁-C₃)alkylene]CO₂H,(C₃-C₅)cycloalkyl, SR⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁷ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl;

R⁸ is H, OH, CO₂H, CO₂R⁷, CF₂C(R⁶)₂OH, C(R⁶)₂OH, C(CF₃)₂OH, SO₂H, SO₃H,CF₂SO₂C(R⁶)₃, CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵,C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)₂,P(O)(OR⁵)OH, P(O)(O)N(H)R⁵, P(O)(C(R⁶)₃)C(R⁶)₃, B(OH)₂, heterocyclyl orheteroaryl;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl oraryl is optionally substituted with 1, 2 or 3 groups selected from OH,CN, SH, SCH₃, SO₂CH₃, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂,NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH₂, C(O)NH(alkyl),CH₂C(O)NH(alkyl), COOH, COOMe, acetyl, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH₂,alkylene-C(O)—NH(Me), NHC(O)alkyl, CH₂—C(O)—(C₁-C₈)alkyl,C(O)—(C₁-C₈)alkyl and alkylcarbonylaminyl, or a cycloalkyl,heterocyclyl, aryl or heteroaryl optionally substituted with OH,halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl orO(C₁-C₈)haloalkyl,

wherein when X⁴ is a bond ring A forms a 5-membered heteroaryl whereinX¹, X⁵ and X⁶ can in addition to the above defined substituents be NR²,and X¹ can in addition be —N-L¹-Y; and

wherein either Q is -L¹-Y, or X¹ is —C-L¹-Y or —N-L¹-Y.

The present invention also provides a pharmaceutical compositioncomprising (i) a therapeutically effective amount of at least onecompound according to Formula I, Formula II, Formula III, Formula IV,Formula V, or Formula VI or a stereoisomer, a tautomer or apharmaceutically acceptable salt thereof; (ii) in combination with apharmaceutically acceptable carrier, diluent or excipient.

Also provided by the present invention is a method for attenuating orinhibiting the activity of eIF4E in at least one cell overexpressingeIF4E, comprising contacting the at least one cell with a compoundaccording to Formula I or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof.

According to the inventive method at least one cell is a colon cancercell, a gastric cancer cell, a thyroid cancer cell, a lung cancer cell,a leukemia cell, a B-cell lymphoma, a T-cell lymphoma, a hairy celllymphoma, Hodgkin's lymphoma cell, non-Hodgkin's lymphoma cell,Burkitt's lymphoma cell, a pancreatic cancer cell, a melanoma cell, amultiple melanoma cell, a brain cancer cell, a CNS cancer cell, a renalcancer cell, a prostate cancer cell, an ovarian cancer cell, or a breastcancer cell.

According to yet another embodiment the invention provides a method fortreating a eIF4E dependent condition in a mammal in need thereofcomprising administering to the mammal (i) a therapeutically effectiveamount of at least one compound according to Formula I, Formula II,Formula III, Formula IV, Formula V, or Formula VI or a stereoisomer,tautomer or pharmaceutically acceptable salt thereof, or (ii) apharmaceutical composition in accordance with the invention.

Compounds and pharmaceutically acceptable formulations in accordancewith the invention are useful for treating an eIF4E dependent conditionsuch as colon cancer, gastric cancer, thyroid cancer, lung cancer,leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma,pancreatic cancer, melanoma, multiple melanoma, brain cancer, CNScancer, renal cancer, prostate cancer, ovarian cancer, or breast cancer.

The above embodiments and other aspects of the invention are readilyapparent in the detailed description that follows. Various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 , graph showing the results of a cell proliferation assay usingcompound 1188.

FIG. 2 , graph showing the results of a cell proliferation assay usingcompound 634.

FIG. 3 , graph showing the results of a cell proliferation assay usingcompound 1141.

DETAILED DESCRIPTION

In the following description certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details. Unless the contextrequires otherwise, throughout the present specification and claims, theword “comprise” and variations thereof, such as, “comprises” and“comprising” are to be construed in an open, inclusive sense (i.e., as“including, but not limited to”).

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Definitions

As used herein, and unless noted to the contrary, the following termsand phrases have the meaning noted below.

“Amino” refers to the —NH₂ substituent.

“Aminocarbonyl” refers to the —C(O)NH₂ substituent.

“Carboxyl” refers to the —CO₂H substituent.

“Carbonyl” refers to a —C(O)—, —(CO)— or —C(═O)— group. All notationsare used interchangeably within the specification.

“Cyano” refers to the —C≡N substituent.

“Cyanoalkylene” refers to the -(alkylene)C≡N substituent.

“Acetyl” refers to the —C(O)CH₃ substituent.

“Hydroxy” or “hydroxyl” refers to the —OH substituent.

“Hydroxyalkylene” refers to the -(alkylene)OH substituent.

“Oxo” refers to a ═O substituent.

“Thio” or “thiol” refer to a —SH substituent.

“Alkyl” refers to a saturated, straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms (C₁-C₁₂ alkyl), from one to eight carbon atoms(C₁-C₈ alkyl) or from one to six carbon atoms (C₁-C₆ alkyl), and whichis attached to the rest of the molecule by a single bond. Exemplaryalkyl groups include methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),3-methylhexyl, 2-methylhexyl, and the like.

“Lower alkyl” has the same meaning as alkyl defined above but havingfrom one to four carbon atoms (C₁-C₄ alkyl).

“Alkenyl” refers to an unsaturated alkyl group having at least onedouble bond and from two to twelve carbon atoms (C₂-C₁₂ alkenyl), fromtwo to eight carbon atoms (C₂-C₈ alkenyl) or from two to six carbonatoms (C₂-C₆ alkenyl), and which is attached to the rest of the moleculeby a single bond, e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl,and the like.

“Alkynyl” refers to an unsaturated alkyl group having at least onetriple bond and from two to twelve carbon atoms (C₂-C₁₂ alkynyl), fromtwo to ten carbon atoms (C₂-C₁₀ alkynyl) from two to eight carbon atoms(C₂-C₈ alkynyl) or from two to six carbon atoms (C₂-C₆ alkynyl), andwhich is attached to the rest of the molecule by a single bond, e.g.,ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon (alkyl) chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, respectively. Alkylenescan have from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like. The alkylene chain is attached tothe rest of the molecule through a single or double bond. The points ofattachment of the alkylene chain to the rest of the molecule can bethrough one carbon or any two carbons within the chain. “Optionallysubstituted alkylene” refers to alkylene or substituted alkylene.

“Alkenylene” refers to divalent alkene. Examples of alkenylene includewithout limitation, ethenylene (—CH═CH—) and all stereoisomeric andconformational isomeric forms thereof. “Substituted alkenylene” refersto divalent substituted alkene. “Optionally substituted alkenylene”refers to alkenylene or substituted alkenylene.

“Alkynylene” refers to divalent alkyne. Examples of alkynylene includewithout limitation, ethynylene, propynylene. “Substituted alkynylene”refers to divalent substituted alkyne.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl having the indicated number of carbon atoms as defined above.Examples of alkoxy groups include without limitation —O-methyl(methoxy), —O-ethyl (ethoxy), —O-propyl (propoxy), —O-isopropyl (isopropoxy) and the like.

“Alkylaminyl” refers to a radical of the formula —NHR_(a) or—NR_(a)R_(a) where each R_(a) is, independently, an alkyl radical havingthe indicated number of carbon atoms as defined above.

“Cycloalkylaminyl” refers to a radical of the formula —NHR_(a) or—NR_(a)R_(a) where R_(a) is a cycloalkyl radical as defined herein.

“Alkylcarbonylaminyl” refers to a radical of the formula —NHC(O)R_(a) or—NR_(a)C(O)R_(a), where R_(a) is an alkyl radical having the indicatednumber of carbon atoms as defined herein.

“Cycloalkylcarbonylaminyl” refers to a radical of the formula—NHC(O)R_(a) or —NR_(a)C(O)R_(a) where R_(a) is a cycloalkyl radical asdefined herein.

“Alkylaminocarbonyl” refers to a radical of the formula —C(O)NHR_(a) or—C(O)NR_(a)R_(a), where each R_(a) is independently, an alkyl radicalhaving the indicated number of carbon atoms as defined herein.

“Cyclolkylaminocarbonyl” refers to a radical of the formula—C(O)NHR_(a), where R_(a) is a cycloalkyl radical as defined herein.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. Exemplary aryls arehydrocarbon ring system radical comprising hydrogen and 6 to 9 carbonatoms and at least one aromatic ring; hydrocarbon ring system radicalcomprising hydrogen and 9 to 12 carbon atoms and at least one aromaticring; hydrocarbon ring system radical comprising hydrogen and 12 to 15carbon atoms and at least one aromatic ring; or hydrocarbon ring systemradical comprising hydrogen and 15 to 18 carbon atoms and at least onearomatic ring. For purposes of this invention, the aryl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. Aryl radicals include, but arenot limited to, aryl radicals derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. “Optionally substituted aryl” refers to an aryl group or asubstituted aryl group.

“Arylene” denotes divalent aryl, and “substituted arylene” refers todivalent substituted aryl.

“Aralkyl” or “araalkylene” may be used interchangeably and refer to aradical of the formula —R_(b)-R_(c) where R_(b) is an alkylene chain asdefined herein and R_(c) is one or more aryl radicals as defined herein,for example, benzyl, diphenylmethyl and the like.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,three to nine carbon atoms, three to eight carbon atoms, three to sevencarbon atoms, three to six carbon atoms, three to five carbon atoms, aring with four carbon atoms, or a ring with three carbon atoms. Thecycloalkyl ring may be saturated or unsaturated and attached to the restof the molecule by a single bond. Monocyclic radicals include, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

“Cycloalkylalkylene” or “cycloalkylalkyl” may be used interchangeablyand refer to a radical of the formula —R_(b)R_(c) where R_(b) is analkylene chain as defined herein and R_(c) is a cycloalkyl radical asdefined herein. In certain embodiments, R_(b) is further substitutedwith a cycloalkyl group, such that the cycloalkylalkylene comprises twocycloalkyl moieties. Cyclopropylalkylene and cyclobutylalkylene areexemplary cycloalkylalkylene groups, comprising at least one cyclopropylor at least one cyclobutyl group, respectively.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo (bromine), chloro (chlorine), fluoro(fluorine), or iodo (iodine).

“Haloalkyl” refers to an alkyl radical having the indicated number ofcarbon atoms, as defined herein, wherein one or more hydrogen atoms ofthe alkyl group are substituted with a halogen (halo radicals), asdefined above. The halogen atoms can be the same or different. Exemplaryhaloalkyls are trifluoromethyl, difluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like.

“Heterocyclyl”, heterocycle”, or “heterocyclic ring” refers to a stable3- to 18-membered saturated or unsaturated radical which consists of twoto twelve carbon atoms and from one to six heteroatoms, for example, oneto five heteroatoms, one to four heteroatoms, one to three heteroatoms,or one to two heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. Exemplary heterocycles include withoutlimitation stable 3-15 membered saturated or unsaturated radicals,stable 3-12 membered saturated or unsaturated radicals, stable 3-9membered saturated or unsaturated radicals, stable 8-membered saturatedor unsaturated radicals, stable 7-membered saturated or unsaturatedradicals, stable 6-membered saturated or unsaturated radicals, or stable5-membered saturated or unsaturated radicals.

Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused, bridged or spiro ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of non-aromatic heterocyclyl radicals include, butare not limited to, oxirane, oxetane, azetidinyl, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, thietanyl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocyclylsinclude heteroaryls as defined herein, and examples of aromaticheterocyclyls are listed in the definition of heteroaryls below.

“Heterocyclylalkyl” or “heterocyclylalkylene” refers to a radical of theformula —R_(b)R_(f) where R_(b) is an alkylene chain as defined hereinand R_(f) is a heterocyclyl radical as defined above, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl maybe attached to the alkyl radical at the nitrogen atom.

“Heteroaryl” or “heteroarylene” refers to a 5- to 14-membered ringsystem radical comprising hydrogen atoms, one to thirteen carbon atoms,one to six heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur, and at least one aromatic ring. For purposes of thisinvention, the heteroaryl radical may be a stable 5-12 membered ring, astable 5-10 membered ring, a stable 5-9 membered ring, a stable 5-8membered ring, a stable 5-7 membered ring, or a stable 6 membered ringthat comprises at least 1 heteroatom, at least 2 heteroatoms, at least 3heteroatoms, at least 4 heteroatoms, at least 5 heteroatoms or at least6 heteroatoms. Heteroaryls may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. The heteroatom may be a member of an aromatic ornon-aromatic ring, provided at least one ring in the heteroaryl isaromatic. Examples include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl).

“Heteroarylalkyl” or “heteroarylalkylene” refers to a radical of theformula —R_(b)R_(g) where R_(b) is an alkylene chain as defined aboveand R_(g) is a heteroaryl radical as defined above.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms, atleast 1-10 carbon atoms, at least 1-8 carbon atoms, at least 1-6 carbonatoms, or at least 1-4 carbon atoms.

“Heterocyclylaminyl” refers to a radical of the formula —NHR_(f) whereR_(f) is a heterocyclyl radical as defined above.

“Thione” refers to a ═S group attached to a carbon atom of a saturatedor unsaturated (C₃-C₈)cyclic or a (C₁-C₈)acyclic moiety.

“Sulfoxide” refers to a —S(O)— group in which the sulfur atom iscovalently attached to two carbon atoms.

“Sulfone” refers to a —S(O)₂— or —(SO₂)— group in which a hexavalentsulfur is attached to each of the two oxygen atoms through double bondsand is further attached to two carbon atoms through single covalentbonds.

The term “oxime” refers to a —C(R_(a))═N—OR_(a) radical where R_(a) ishydrogen, lower alkyl, an alkylene or arylene group as defined above.

The compound of the invention can exist in various isomeric forms, aswell as in one or more tautomeric forms, including both single tautomersand mixtures of tautomers. The term “isomer” is intended to encompassall isomeric forms of a compound of this invention, including tautomericforms of the compound.

Some compounds described here can have asymmetric centers and thereforeexist in different enantiomeric and diastereomeric forms. A compound ofthe invention can be in the form of an optical isomer or a diastereomer.Accordingly, the invention encompasses compounds of the invention andtheir uses as described herein in the form of their optical isomers,diastereoisomers and mixtures thereof, including a racemic mixture.Optical isomers of the compounds of the invention can be obtained byknown techniques such as asymmetric synthesis, chiral chromatography, orvia chemical separation of stereoisomers through the employment ofoptically active resolving agents.

Unless otherwise indicated “stereoisomer” means one stereoisomer of acompound that is substantially free of other stereoisomers of thatcompound. Thus, a stereomerically pure compound having one chiral centerwill be substantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, for example greater than about 90%by weight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, or greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, or greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

If there is a discrepancy between a depicted structure and a name givento that structure, then the depicted structure controls. Additionally,if the stereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it. In some cases, however, where more than one chiralcenter exists, the structures and names may be represented as singleenantiomers to help describe the relative stereochemistry. Those skilledin the art of organic synthesis will know if the compounds are preparedas single enantiomers from the methods used to prepare them.

In this description a “pharmaceutically acceptable salt” is apharmaceutically acceptable, organic or inorganic acid or base salt of acompound of the invention. Representative pharmaceutically acceptablesalts include, e.g., alkali metal salts, alkali earth salts, ammoniumsalts, water-soluble and water-insoluble salts, such as the acetate,amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate,esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts. Apharmaceutically acceptable salt can have more than one charged atom inits structure. In this instance the pharmaceutically acceptable salt canhave multiple counterions. Thus, a pharmaceutically acceptable salt canhave one or more charged atoms and/or one or more counterions.

The terms “treat”, “treating” and “treatment” refer to the ameliorationor eradication of a disease or symptoms associated with a disease. Incertain embodiments, such terms refer to minimizing the spread orworsening of the disease resulting from the administration of one ormore prophylactic or therapeutic agents to a patient with such adisease. In the context of the present invention the terms “treat”,“treating” and “treatment” also refer to:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or(iv) relieving the symptoms resulting from the disease or condition,i.e., relieving pain without addressing the underlying disease orcondition. As used herein, the terms “disease” and “condition” may beused interchangeably or may be different in that the particular maladyor condition may not have a known causative agent (so that etiology hasnot yet been worked out) and it is therefore not yet recognized as adisease but only as an undesirable condition or syndrome, wherein a moreor less specific set of symptoms have been identified by clinicians.

The term “effective amount” refers to an amount of a compound of theinvention or other active ingredient sufficient to provide a therapeuticor prophylactic benefit in the treatment or prevention of a disease orto delay or minimize symptoms associated with a disease. Further, atherapeutically effective amount with respect to a compound of theinvention means that amount of therapeutic agent alone, or incombination with other therapies, that provides a therapeutic benefit inthe treatment or prevention of a disease. Used in connection with acompound of the invention, the term can encompass an amount thatimproves overall therapy, reduces or avoids symptoms or causes ofdisease, or enhances the therapeutic efficacy or synergies with anothertherapeutic agent.

The term “inhibit” or “inhibitor” refers to an alteration, interference,reduction, down regulation, blocking, suppression, abrogation ordegradation, directly or indirectly, in the expression, amount oractivity of a target gene, target protein, or signaling pathway relativeto (1) a control, endogenous or reference target or pathway, or (2) theabsence of a target or pathway, wherein the alteration, interference,reduction, down regulation, blocking, suppression, abrogation ordegradation is statistically, biologically, or clinically significant.The term “inhibit” or “inhibitor” includes gene “knock out” and gene“knock down” methods, such as by chromosomal editing.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function, or activity of, forexample, eukaryotic initiation factor 4E (eIF4E). “Modulation”, in itsvarious forms, is intended to encompass inhibition, antagonism, partialantagonism, activation, agonism and/or partial agonism of the activityassociated with eIF4E. eIF4E inhibitors are compounds that bind to,partially or totally block stimulation, decrease, prevent, delayactivation, inactivate, desensitize, or down regulate signaltransduction. The ability of a compound to modulate eIF4E activity canbe demonstrated in an enzymatic assay or a cell-based assay.

A “patient” or subject” includes an animal, such as a human, cow, horse,sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbitor guinea pig. The animal can be a mammal such as a non-primate and aprimate (e.g., monkey and human). In one embodiment, a patient is ahuman, such as a human infant, child, adolescent or adult.

The term “prodrug” refers to a precursor of a drug, a compound whichupon administration to a patient, must undergo chemical conversion bymetabolic processes before becoming an active pharmacological agent.Exemplary prodrugs of compounds in accordance with Formula I are esters,acetamides, and amides.

Compounds of the Invention

The present invention generally is directed to compounds encompassed bythe genus of Formula I, or stereoisomers, tautomers or pharmaceuticallyacceptable salts thereof.

In one embodiment, the invention is directed to compounds according toFormula II

or stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein:

X² and X⁵ are independently CR² or N,

-   -   or when X² is CR², R¹ and R² together with the atoms they        attached to form a 6-membered aryl or heteroaryl;

L¹ is —(CH₂)—, —(CH₂)₂—, —(CH₂)₃—, —CH((C₁-C₈)alkyl)(CH₂)—,—CH((C₁-C₈)alkyl)(CH₂)₂—, —(CH₂)₂—O—, —CH₂CH═CH—, —CH₂C≡C— or—CH₂(cyclopropyl)-;

L² is —C(R⁶)(R⁶)—, —C(R⁶)(R⁶)C(R⁶)(R⁶)—, —C(R⁶)═C(R⁶)—,—N(R⁵)C(R⁶)(R⁶)—, —OC(R⁶)(R⁶)—, —C(═O)—, —C(═O)N(R⁵)C(R⁶)(R⁶)— or abond;

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

R¹ is H, OH, halo, CN, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₆)cycloalkylor NR⁵R⁵;

R² is independently H, halo, CN, NO, NO₂, C≡H, (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, CH₂SR⁵, OR⁵, NHR⁵, NR⁵R⁵,[(C₁-C₈)alkylene]heterocyclyl, [(C₁-C₈)alkylene]heteroaryl,[(C₁-C₈)alkylene]NHR⁵, [(C₁-C₈)alkylene]NR⁵R⁵, [(C₁-C₈)alkylyne]NR⁵R⁵,C(O)R⁵, C(O)OR⁵, C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO₂R⁵, SO₂NHR⁵,SO₂NR⁵R⁵, NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl orheterocyclyl;

R³ is independently OH, halo, CN, NO₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₁-C₆)alkoxy, C≡H, NHR⁷, NR⁷R⁷, CO₂H, CO₂R⁷, [(C₁-C₃)alkylene](C₁-C₃)alkoxy, [(C₁-C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, ═O. ═S, SR⁷,SO₂R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁵ is independently H, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₃-C₅)cycloalkyl, CO₂H, [(C₁-C₃)alkylene]heteroaryl,[(C₁-C₃)alkylene]aryl, [(C₁-C₃)alkylene]CO₂H, heterocyclyl, aryl orheteroaryl,

or wherein two R⁵ substituents together with a nitrogen atom form a 4-,5-, 6-, or 7-membered heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy, NHR⁷, NR⁷R⁷, CO₂H, [(C₁-C₃)alkylene]CO₂H,(C₃-C₅)cycloalkyl, SR⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁷ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl;

R⁸ is H, OH, CO₂H, CO₂R⁷, CF₂C(R⁶)₂OH, C(R⁶)₂OH, C(CF₃)₂OH, SO₂H, SO₃H,CF₂SO₂C(R⁶)₃, CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵,C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)₂,P(O)(OR⁵)OH, P(O)(O)N(H)R⁵, P(O)(C(R⁶)₃)C(R⁶)₃, B(OH)₂, heterocyclyl orheteroaryl;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl oraryl is optionally substituted with 1, 2 or 3 groups selected from OH,CN, SH, SCH₃, SO₂CH₃, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂,NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH₂, C(O)NH(alkyl),CH₂C(O)NH(alkyl), COOH, COOMe, acetyl, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH₂,alkylene-C(O)—NH(Me), NHC(O)alkyl, CH₂—C(O)—(C₁-C₈)alkyl,C(O)—(C₁-C₈)alkyl and alkylcarbonylaminyl, or a cycloalkyl,heterocyclyl, aryl or heteroaryl optionally substituted with OH,halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl orO(C₁-C₈)haloalkyl.

In another embodiment the invention is directed to compounds of FormulaIII

or stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein:

L¹ is —(CH₂)—, —(CH₂)₂—, —(CH₂)₃—, —CH((C₁-C₈)alkyl)(CH₂)—,—CH((C₁-C₈)alkyl)(CH₂)₂—, —(CH₂)₂—O—, —CH₂CH═CH—, —CH₂C≡C— or—CH₂(cyclopropyl)-;

L² is —C(R⁶)(R⁶)—, —C(R⁶)(R⁶)C(R⁶)(R⁶)—, —C(R⁶)═C(R⁶)—,—N(R⁵)C(R⁶)(R⁶)—, —OC(R⁶)(R⁶)—, —C(═O)—, —C(═O)N(R⁵)C(R⁶)(R⁶)— or abond; Ring C is a heteroaryl;

R¹ is H, OH, halo, CN, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₆)cycloalkylor NR⁵R⁵;

R² is independently H, halo, CN, NO, NO₂, C≡H, (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, CH₂SR⁵, OR⁵, NHR⁵, NR⁵R⁵,[(C₁-C₈)alkylene]heterocyclyl, [(C₁-C₈)alkylene]heteroaryl,[(C₁-C₈)alkylene]NHR⁵, [(C₁-C₈)alkylene]NR⁵R⁵, [(C₁-C₈)alkylyne]NR⁵R⁵,C(O)R⁵, C(O)OR⁵, C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO₂R⁵, SO₂NHR⁵,SO₂NR⁵R⁵, NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl orheterocyclyl;

R³ is independently OH, halo, CN, NO₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₁-C₆)alkoxy, C≡H, NHR⁷, NR⁷R⁷, CO₂H, CO₂R⁷, [(C₁-C₃)alkylene](C₁-C₃)alkoxy, [(C₁-C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, ═O. ═S, SR⁷,SO₂R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁵ is independently H, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₃-C₅)cycloalkylor heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy, NHR⁷, NR⁷R⁷, CO₂H, [(C₁-C₃)alkylene]CO₂H,(C₃-C₅)cycloalkyl, SR⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁷ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl;

R⁸ is H, OH, CO₂H, CO₂R⁷, CF₂C(R⁶)₂OH, C(R⁶)₂OH, C(CF₃)₂OH, SO₂H, SO₃H,CF₂SO₂C(R⁶)₃, CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵,C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)₂,P(O)(OR⁵)OH, P(O)(O)N(H)R⁵, P(O)(C(R⁶)₃)C(R⁶)₃, B(OH)₂, heterocyclyl orheteroaryl; R⁹ is H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl orheterocyclyl;

m is 0, 1, or 2;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl oraryl is optionally substituted with 1, 2 or 3 groups selected from OH,CN, SH, SCH₃, SO₂CH₃, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂,NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH₂, C(O)NH(alkyl),CH₂C(O)NH(alkyl), COOH, COOMe, acetyl, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH₂,alkylene-C(O)—NH(Me), NHC(O)alkyl, CH₂—C(O)—(C₁-C₈)alkyl,C(O)—(C₁-C₈)alkyl and alkylcarbonylaminyl.

In one embodiment, the invention is directed to compounds according toFormula IV

or stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein:

X² and X⁵ are independently CR² or N,

-   -   or when X² is CR², R¹ and R² together with the atoms they        attached to form a 6-membered aryl or heteroaryl;

X³ is C, or X³ is C or N when X⁴ is a bond;

X⁴ is a bond, CR² or N,

-   -   wherein X⁴ and X⁵ together with 3 or 4 carbon or nitrogen atoms        combine to form a 5- or 6-membered heteroaryl;

L¹ is —(CH₂)—, —(CH₂)₂—, —(CH₂)₃—, —CH((C₁-C₈)alkyl)(CH₂)—,—CH((C₁-C₈)alkyl)(CH₂)₂—, —(CH₂)₂—O—, —CH₂CH═CH—, —CH₂C≡C— or—CH₂(cyclopropyl)-;

L² is —C(R⁶)(R⁶)—, —C(R⁶)(R⁶)C(R⁶)(R⁶)—, —C(R⁶)═C(R⁶)—,—N(R⁵)C(R⁶)(R⁶)—, —OC(R⁶)(R⁶)—, —C(═O)—, —C(═O)N(R⁵)C(R⁶)(R⁶)—;

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

R¹ is H, OH, halo, CN, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₆)cycloalkylor NR⁵R⁵;

R² is independently H, halo, CN, NO, NO₂, C≡H, (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, CH₂SR⁵, OR⁵, NHR⁵, NR⁵R⁵,[(C₁-C₈)alkylene]heterocyclyl, [(C₁-C₈)alkylene]heteroaryl,[(C₁-C₈)alkylene]NHR⁵, [(C₁-C₈)alkylene]NR⁵R⁵, [(C₁-C₈)alkylyne]NR⁵R⁵,C(O)R⁵, C(O)OR⁵, C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO₂R⁵, SO₂NHR⁵,SO₂NR⁵R⁵, NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl orheterocyclyl;

R³ is independently OH, halo, CN, NO₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₁-C₆)alkoxy, C≡H, NHR⁷, NR⁷R⁷, CO₂H, CO₂R⁷, [(C₁-C₃)alkylene](C₁-C₃)alkoxy, [(C₁-C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, ═O. ═S, SR⁷,SO₂R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁵ is independently H, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₃-C₅)cycloalkyl, CO₂H, [(C₁-C₃)alkylene]heteroaryl,[(C₁-C₃)alkylene]aryl, [(C₁-C₃)alkylene]CO₂H, heterocyclyl, aryl orheteroaryl,

or wherein two R⁵ substituents together with a nitrogen atom form a 4-,5-, 6- or 7-membered heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy, NHR⁷, NR⁷R⁷, CO₂H, [(C₁-C₃)alkylene]CO₂H,(C₃-C₅)cycloalkyl, SR⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁷ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl;

R⁸ is H, OH, CO₂H, CO₂R⁷, CF₂C(R⁶)₂OH, C(R⁶)₂OH, C(CF₃)₂OH, SO₂H, SO₃H,CF₂SO₂C(R⁶)₃, CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵,C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)₂,P(O)(OR⁵)OH, P(O)(O)N(H)R⁵, P(O)(C(R⁶)₃)C(R⁶)₃, B(OH)₂, heterocyclyl orheteroaryl;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl oraryl is optionally substituted with 1, 2 or 3 groups selected from OH,CN, SH, SCH₃, SO₂CH₃, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂,NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH₂, C(O)NH(alkyl),CH₂C(O)NH(alkyl), COOH, COOMe, acetyl, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH₂,alkylene-C(O)—NH(Me), NHC(O)alkyl, CH₂—C(O)—(C₁-C₈)alkyl,C(O)—(C₁-C₈)alkyl and alkylcarbonylaminyl, or a cycloalkyl,heterocyclyl, aryl or heteroaryl optionally substituted with OH,halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl orO(C₁-C₈)haloalkyl,

wherein when X⁴ is a bond, ring A forms a 5-membered heteroaryl whereinX¹ and X⁵ can in addition to C be N.

In another embodiment the invention is directed to compounds of FormulaV

or stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein:

Q is -L¹-Y;

L¹ is —(CH₂)—, —(CH₂)₂—, —(CH₂)₃—, —CH((C₁-C₈)alkyl)(CH₂)—,—CH((C₁-C₈)alkyl)(CH₂)₂—, —(CH₂)₂—O—, —CH₂CH═CH—, —CH₂C≡C— or—CH₂(cyclopropyl)-;

Y is

wherein

Ring B is a six-membered aryl, heteroaryl or heterocyclyl;

R¹ is H, OH, halo, CN, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₆)cycloalkylor NR⁵R⁵;

R² is independently H, halo, CN, NO, NO₂, C≡H, (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, CH₂SR⁵, OR⁵, NHR⁵, NR⁵R⁵,[(C₁-C₈)alkylene]heterocyclyl, [(C₁-C₈)alkylene]heteroaryl,[(C₁-C₈)alkylene]NHR⁵, [(C₁-C₈)alkylene]NR⁵R⁵, [(C₁-C₈)alkylyne]NR⁵R⁵,C(O)R⁵, C(O)OR⁵, C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO₂R⁵, SO₂NHR⁵,SO₂NR⁵R⁵, NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl orheterocyclyl;

R³ is independently OH, halo, CN, NO₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₁-C₆)alkoxy, C≡H, NHR⁷, NR⁷R⁷, CO₂H, CO₂R⁷, [(C₁-C₃)alkylene](C₁-C₃)alkoxy, [(C₁-C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, ═O. ═S, SR⁷,SO₂R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁴ is H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy,SR⁷ or Z, wherein Z is

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

L² is —C(R⁶)(R⁶)—, —C(R⁶)(R⁶)C(R⁶)(R⁶)—, —C(R⁶)═C(R⁶)—,—N(R⁵)C(R⁶)(R⁶)—, —OC(R⁶)(R⁶)—, —C(═O)—, —C(═O)N(R⁵)C(R⁶)(R⁶)— or abond;

R⁵ is independently H, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₃-C₅)cycloalkyl, CO₂H, [(C₁-C₃)alkylene]heteroaryl,[(C₁-C₃)alkylene]aryl, [(C₁-C₃)alkylene]CO₂H, heterocyclyl, aryl orheteroaryl,

or wherein two R⁵ substituents together with a nitrogen atom form a 4-,5-, or 6-membered heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy, NHR⁷, NR⁷R⁷, CO₂H, [(C₁-C₃)alkylene]CO₂H,(C₃-C₅)cycloalkyl, SR⁷, NH(CO)R⁷ or

NR⁷(CO)R⁷; R⁷ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl;

R⁸ is H, OH, CO₂H, CO₂R⁷, CF₂C(R⁶)₂OH, C(R⁶)₂OH, C(CF₃)₂OH, SO₂H, SO₃H,CF₂SO₂C(R⁶)₃, CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵,C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, P(O)(OR⁵)OH,P(O)(O)N(H)R⁵, P(O)(C(R⁶)₃)C(R⁶)₃, B(OH)₂, heterocyclyl or heteroaryl;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1, 2, 3 or 4;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl oraryl is optionally substituted with 1, 2 or 3 groups selected from OH,CN, SH, SCH₃, SO₂CH₃, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂,NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH₂, C(O)NH(alkyl),CH₂C(O)NH(alkyl), COOH, COOMe, acetyl, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH₂,alkylene-C(O)—NH(Me), NHC(O)alkyl, CH₂—C(O)—(C₁-C₈)alkyl,C(O)—(C₁-C₈)alkyl and alkylcarbonylaminyl, or a cycloalkyl,heterocyclyl, aryl or heteroaryl optionally substituted with OH,halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl orO(C₁-C₈)haloalkyl.

In another embodiment the invention is directed to compounds of FormulaVI

or stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein:

Q is -L¹-Y;

L¹ is —(CH₂)—, —(CH₂)₂—, —(CH₂)₃—, —CH((C₁-C₈)alkyl)(CH₂)—,—CH((C₁-C₈)alkyl)(CH₂)₂—, —(CH₂)₂—O—, —CH₂CH═CH—, —CH₂C≡C— or—CH₂(cyclopropyl)-;

Y is

wherein

Ring B is a six-membered aryl, heteroaryl or heterocyclyl;

R¹ is H, OH, halo, CN, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₆)cycloalkylor NR⁵R⁵;

R² is independently H, halo, CN, NO, NO₂, C≡H, (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, CH₂SR⁵, OR⁵, NHR⁵, NR⁵R⁵,[(C₁-C₈)alkylene]heterocyclyl, [(C₁-C₈)alkylene]heteroaryl,[(C₁-C₈)alkylene]NHR⁵, [(C₁-C₈)alkylene]NR⁵R⁵, [(C₁-C₈)alkylyne]NR⁵R⁵,C(O)R⁵, C(O)OR⁵, C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO₂R⁵, SO₂NHR⁵,SO₂NR⁵R⁵, NH(CO)R⁶, NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl orheterocyclyl;

R³ is independently OH, halo, CN, NO₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₁-C₆)alkoxy, C≡H, NHR⁷, NR⁷R⁷, CO₂H, CO₂R⁷, [(C₁-C₃)alkylene](C₁-C₃)alkoxy, [(C₁-C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, ═O. ═S, SR⁷,SO₂R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁴ is H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy,SR⁷ or Z, wherein Z is

Ring C is cycloalkyl, heterocyclyl, aryl or heteroaryl;

L² is —C(R⁶)(R⁶)—, —C(R⁶)(R⁶)C(R⁶)(R⁶)—, —C(R⁶)═C(R⁶)—,—N(R⁵)C(R⁶)(R⁶)—, —OC(R⁶)(R⁶)—, —C(═O)—, —C(═O)N(R⁵)C(R⁶)(R⁶)— or abond;

R⁵ is independently H, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₃-C₅)cycloalkyl, CO₂H, [(C₁-C₃)alkylene]heteroaryl,[(C₁-C₃)alkylene]aryl, [(C₁-C₃)alkylene]CO₂H, heterocyclyl, aryl orheteroaryl,

or wherein two R⁵ substituents together with a nitrogen atom form a 4-,5-, or 6-membered heterocyclyl;

R⁶ is independently H, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkoxy, NHR⁷, NR⁷R⁷, CO₂H, [(C₁-C₃)alkylene]CO₂H,(C₃-C₅)cycloalkyl, SR⁷, NH(CO)R⁷ or NR⁷(CO)R⁷;

R⁷ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl;

R⁸ is H, OH, CO₂H, CO₂R⁷, CF₂C(R⁶)₂OH, C(R⁶)₂OH, C(CF₃)₂OH, SO₂H, SO₃H,CF₂SO₂C(R⁶)₃, CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵,C(O)haloalkyl, C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)₂,P(O)(OR⁵)OH, P(O)(O)N(H)R⁵, P(O)(C(R⁶)₃)C(R⁶)₃, B(OH)₂, heterocyclyl orheteroaryl;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 0, 1, 2, 3 or 4;

wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl oraryl is optionally substituted with 1, 2 or 3 groups selected from OH,CN, SH, SCH₃, SO₂CH₃, SO₂NH₂, SO₂NH(C₁-C₄)alkyl, halogen, NH₂,NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂, NH(aryl), C(O)NH₂, C(O)NH(alkyl),CH₂C(O)NH(alkyl), COOH, COOMe, acetyl, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH₂,alkylene-C(O)—NH(Me), NHC(O)alkyl, CH₂—C(O)—(C₁-C₈)alkyl,C(O)—(C₁-C₈)alkyl and alkylcarbonylaminyl, or a cycloalkyl,heterocyclyl, aryl or heteroaryl optionally substituted with OH,halogen, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl orO(C₁-C₈)haloalkyl.

In one embodiment X² of Formulae I, II, and IV is N.

In one embodiment X³ of Formulae I and IV is C.

In one embodiment X⁴ of Formulae I and IV is CR² or N.

In one embodiment X⁵ of Formulae I and IV is CR².

In one embodiment L¹ of Formulae I, II, III, IV, V and VI is —(CH₂)₂—O—,—CH₂CH═CH— or —CH₂C≡C—. In another embodiment L¹ is —(CH₂)₂—O—.

In one embodiment L² of Formulae I, II, III, IV, V and VI is a bond.

In one embodiment Ring B of Formulae I, V and VI is aryl.

In one embodiment Ring C of Formulae I, II, III, IV, V and VI isheteroaryl.

In one embodiment Ring C of Formulae I, II, III, IV, V and VI is

In one embodiment Ring C of Formula III is

In one embodiment R¹ of Formulae I, II, III, IV, V and VI is H,(C₁-C₈)alkyl or (C₁-C₈)haloalkyl.

In one embodiment R¹ of Formula IV is NHR⁵ or N[(C₁-C₃)alkyl](R⁵).

In one embodiment R² of Formulae I, II, III, IV, V and VI is halo, CN,(C₁-C₈)alkyl, (C₁-C₈)haloalkyl or OR⁵. In another embodiment R² is halo,CN or (C₁-C₈)haloalkyl.

In one embodiment R³ of Formulae I, II, III, IV, V and VI is halo, CN,(C₁-C₃)alkyl or (C₁-C₃)haloalkyl.

In one embodiment R⁴ of Formulae I, V and VI is Z, wherein Z is

In one embodiment R⁵ of Formulae I, II, III, V and VI is H, (C₁-C₃)alkylor (C₁-C₃)haloalkyl. In another embodiment R⁵ of Formula IV is aryl. Inanother embodiment R⁵ of Formulae I, II, III, IV, V, and VI is H,(C₁-C₃)alkyl or (C₁-C₃)haloalkyl.

In one embodiment R⁶ of Formulae I, II, III, IV, V and VI is H, OH,halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl or (C₁-C₃)alkoxy.

In one embodiment R⁷ of Formulae I, II, III, IV, V and VI is H,(C₁-C₈)alkyl or (C₁-C₈)haloalkyl.

In one embodiment R⁸ of Formulae I, II, III, IV, V and VI is CO₂H orC(O)N(H)SO₂R⁵.

In one embodiment R⁹ of Formula III is (C₁-C₈)alkyl or (C₁-C₈)haloalkyl.

In one embodiment R⁹ of Formula III is cycloalkyl or heterocyclyl.

In one embodiment “m” of Formulae I and II=2 or 3. In another embodiment“n” of Formulae I, II, IV, V and VI=1 or 2. In yet another embodiment“p” of Formulae I, II, III, IV, V and VI=0 or 1.

In one embodiment the optional substituents of alkyl, cycloalkyl,heterocyclyl, heteroaryl or aryl are OH, CN, halogen, (C₁-C₈)alkyl,O(C₁-C₈)alkyl, haloalkyl, alkylene-C(O)NH₂ or alkylene-C(O)—NH(Me).

In one embodiment the optional substituents of alkyl, cycloalkyl,heterocyclyl, heteroaryl or aryl are cycloalkyl, heterocyclyl, aryl orheteroaryl optionally substituted with OH, halogen, (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, O(C₁-C₈)alkyl or O(C₁-C₈)haloalkyl.

In one embodiment, the compounds according to Formulae I, II, III, IV, Vand VI are selected from compounds 1-1250.

The inventive compounds according to Formulae I, II, III, IV, V and VImay be isotopically-labeled by having one or more atoms replaced by anatom having a different atomic mass or mass number. Examples of isotopesthat can be incorporated into compounds according to Formulae I, II,III, IV, V and VI include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine, chlorine, or iodine. Illustrative of suchisotopes are ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P,³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. These radiolabeledcompounds can be used to measure the biodistribution, tissueconcentration and the kinetics of transport and excretion frombiological tissues including a subject to which such a labeled compoundis administered. Labeled compounds are also used to determinetherapeutic effectiveness, the site or mode of action, and the bindingaffinity of a candidate therapeutic to a pharmacologically importanttarget. Certain radioactive-labeled compounds according to Formulae I,II, III, IV, V and VI, therefore, are useful in drug and/or tissuedistribution studies. The radioactive isotopes tritium, i.e. ³H, andcarbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view oftheir ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, affordscertain therapeutic advantages resulting from the greater metabolicstability, for example, increased in vivo half-life of compoundscontaining deuterium. Substitution of hydrogen with deuterium may reducedose required for therapeutic effect, and hence may be preferred in adiscovery or clinical setting.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, provides labeled analogs of the inventive compounds that are usefulin Positron Emission Tomography (PET) studies, e.g., for examiningsubstrate receptor occupancy. Isotopically-labeled compounds accordingto Formulae I, II, III, IV, V and VI can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described in the Preparations and Examplessection as set out below using an appropriate isotopic-labeling reagent.

Embodiments of the invention disclosed herein are also meant toencompass the in vivo metabolic products of compounds according toFormulae I, II, III, IV, V and VI. Such products may result from, forexample, the oxidation, reduction, hydrolysis, amidation,esterification, and like processes primarily due to enzymatic activityupon administration of a compound of the invention. Accordingly, theinvention includes compounds that are produced as by-products ofenzymatic or non-enzymatic activity on an inventive compound followingthe administration of such a compound to a mammal for a period of timesufficient to yield a metabolic product. Metabolic products,particularly pharmaceutically active metabolites are typicallyidentified by administering a radiolabeled compound of the invention ina detectable dose to a subject, such as rat, mouse, guinea pig, monkey,or human, for a sufficient period of time during which metabolismoccurs, and isolating the metabolic products from urine, blood or otherbiological samples that are obtained from the subject receiving theradiolabeled compound.

The invention also provides pharmaceutically acceptable salt forms ofcompounds in Formulae I, II, III, IV, V and VI. Encompassed within thescope of the invention are both acid and base addition salts that areformed by contacting a pharmaceutically suitable acid or apharmaceutically suitable base with a compound of the invention.

To this end, a “pharmaceutically acceptable acid addition salt” refersto those salts which retain the biological effectiveness and propertiesof the free bases, which are not biologically or otherwise undesirable,and which are formed with inorganic acids such as, but are not limitedto, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

Similarly, a “pharmaceutically acceptable base addition salt” refers tothose salts which retain the biological effectiveness and properties ofthe free acids, which are not biologically or otherwise undesirable.These salts are prepared by addition of an inorganic base or an organicbase to the free acid. Salts derived from inorganic bases include, butare not limited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

Compounds of the invention or their pharmaceutically acceptable saltsmay contain one or more asymmetric centers and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

The term “tautomer” refers to a proton shift from one atom of a moleculeto another atom of the same molecule. For example:

The compounds provided in this disclosure may be depicted as differenttautomers, and when compounds have tautomeric forms, all tautomericforms are intended to be within the scope of the invention, and thenaming of a compound does not exclude any tautomer of that compound.

The inventive compounds are synthesized using conventional syntheticmethods, and more specifically using the general methods noted below.

Pharmaceutical Formulations

In one embodiment compounds according to Formulae I, II, III, IV, V andVI are formulated as pharmaceutically acceptable compositions thatcontain compounds of Formulae I, II, III, IV, V and VI in an amounteffective to treat a particular disease or condition of interest uponadministration of the pharmaceutical composition to a mammal.Pharmaceutical compositions in accordance with the present invention cancomprise compounds of Formulae I, II, III, IV, V and VI in combinationwith a pharmaceutically acceptable carrier, diluent or excipient.

In this regard, a “pharmaceutically acceptable carrier, diluent orexcipient” includes without limitation any adjuvant, carrier, excipient,glidant, sweetening agent, diluent, preservative, dye/colorant, flavorenhancer, surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

Further, a “mammal” includes humans and both domestic animals such aslaboratory animals and household pets (e.g., cats, dogs, swine, cattle,sheep, goats, horses, rabbits), and non-domestic animals such aswildlife and the like.

The pharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration. When intended for oraladministration, the pharmaceutical composition is preferably in eithersolid or liquid form, where semi-solid, semi-liquid, suspension and gelforms are included within the forms considered herein as either solid orliquid.

As a solid composition for oral administration the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device.

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared by anymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

In certain embodiments a pharmaceutical composition comprising acompound of Formulae I, II, III, IV, V and VI is administered to amammal in an amount sufficient to inhibit eIF4E activity uponadministration, and preferably with acceptable toxicity to the same.eIF4E activity of Formulae I, II, III, IV, V and VI compounds can bedetermined by one skilled in the art, for example, as described in theExamples below. Appropriate concentrations and dosages can be readilydetermined by one skilled in the art.

Therapeutic Use

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy.

“Effective amount” or “therapeutically effective amount” refers to thatamount of a compound of the invention which, when administered to amammal, preferably a human, is sufficient to effect treatment, asdefined below, of a eIF4E related condition or disease in the mammal,preferably a human. The amount of a compound of the invention whichconstitutes a “therapeutically effective amount” will vary depending onthe compound, the condition and its severity, the manner ofadministration, and the age of the mammal to be treated, but can bedetermined routinely by one of ordinary skill in the art having regardto his own knowledge and to this disclosure.

Compounds of the invention or pharmaceutically acceptable salt thereofmay also be administered simultaneously with, prior to, or afteradministration of one or more other therapeutic agents. Such combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound of the invention and one or moreadditional active agents, as well as administration of the compound ofthe invention and each active agent in its own separate pharmaceuticaldosage formulation. For example, a compound of the invention and theother active agent can be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent administered in separate oral dosage formulations. Where separatedosage formulations are used, the compounds of the invention and one ormore additional active agents can be administered at essentially thesame time, i.e., concurrently, or at separately staggered times, i.e.,sequentially; combination therapy is understood to include all theseregimens.

In certain embodiments the disclosed compounds are useful for inhibitingthe activity of eIF4E and/or can be useful in analyzing eIF4E signalingactivity in model systems and/or for preventing, treating, orameliorating a symptom associated with a disease, disorder, orpathological condition involving eIF4E, preferably one afflictinghumans. A compound which inhibits the activity of eIF4E will be usefulin preventing, treating, ameliorating, or reducing the symptoms orprogression of diseases of uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses or diseases which areaccompanied with uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses, particularly in which the uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ismediated by eIF4E, such as, for example, haematological tumors, solidtumors, and/or metastases thereof, including leukemias andmyelodysplastic syndrome, malignant lymphomas, for example, B-celllymphoma, T-cell lymphoma, hairy cell lymphoma, Hodgkin's lymphoma,non-Hodgins lymphoma and Burkitt's lymphoma, head and neck tumorsincluding brain tumors and brain metastases, tumors of the thoraxincluding non-small cell and small cell lung tumors, gastrointestinaltumors, endocrine tumors, mammary and other gynecological tumors,urological tumors including renal, bladder and prostate tumors, skintumors, and sarcomas, and/or metastases thereof.

Furthermore, the inventive compounds and their pharmaceuticalcompositions are candidate therapeutics for the prophylaxis and/ortherapy of cytokine related diseases, such as inflammatory diseases,allergies, or other conditions associated with proinflammatorycytokines. Exemplary inflammatory diseases include without limitation,chronic or acute inflammation, inflammation of the joints such aschronic inflammatory arthritis, rheumatoid arthritis, psoriaticarthritis, osteoarthritis, juvenile rheumatoid arthritis, Reiter'ssyndrome, rheumatoid traumatic arthritis, rubella arthritis, acutesynovitis and gouty arthritis; inflammatory skin diseases such assunburn, psoriasis, erythrodermic psoriasis, pustular psoriasis, eczema,dermatitis, acute or chronic graft formation, atopic dermatitis, contactdermatitis, urticaria and scleroderma; inflammation of thegastrointestinal tract such as inflammatory bowel disease, Crohn'sdisease and related conditions, ulcerative colitis, colitis, anddiverticulitis; nephritis, urethritis, salpingitis, oophoritis,endomyometritis, spondylitis, systemic lupus erythematosus and relateddisorders, multiple sclerosis, asthma, meningitis, myelitis,encephalomyelitis, encephalitis, phlebitis, thrombophlebitis,respiratory diseases such as asthma, bronchitis, chronic obstructivepulmonary disease (COPD), inflammatory lung disease and adultrespiratory distress syndrome, and allergic rhinitis; endocarditis,osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumaticendocarditis, rheumatic myocarditis, rheumatic mitral valve disease,rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjögren's syndrome, neuroinflammatory disease, sepsis, conjunctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis.oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, Goodpasture's disease, crescenticglomerulonephritis, pancreatitis, endomyometritis, myometritis,metritis, cervicitis, endocervicitis, exocervicitis, parametritis,tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

Yet further, the inventive compounds and their pharmaceuticalcompositions are candidate therapeutics for the prophylaxis and/ortherapy of fibrotic diseases, such as various forms of fibrosis,fibromas or any disease giving rise to fibrosis whether as a main or asecondary symptom. Exemplary fibrotic diseases include withoutlimitation, viral hepatitis, hepatic fibrosis, schistosomiasis,steatohepatitis (alcoholic or non-alcoholic), cirrhosis, idiopathicpulmonary fibrosis (IPF), systemic sclerosis (scleroderma), nephrogenicsystemic fibrosis (NSF), diabetes, untreated hypertension, heart attack,hypertension, atherosclerosis, restenosis, macular degeneration, retinaland vitreal retinopathy, keloids, hypertrophic scars, Crohn's diseaseand Alzheimer's disease.

Although inflammation is the unifying pathogenic process of thesediseases, current therapies only treat the symptoms of the disease andnot the underlying cause of inflammation. The compositions of thepresent invention are useful for the treatment and/or prophylaxis ofinflammatory diseases and related complications and disorders.

Accordingly, certain embodiments are directed to a method for treating aeIF4E dependent condition in a mammal in need thereof, the methodcomprising administering an effective amount of a pharmaceuticalcomposition as described above (i.e., a pharmaceutical compositioncomprising one or more compounds of Formulae I, II, III, IV, V and VI)to a mammal.

As described above deregulation of protein synthesis is a common eventin human cancers. A key regulator of translational control is eIF4Ewhose activity is a key determinant of tumorigenicity. Inhibitors ofeIF4E are suitable candidate therapeutics for treating cellproliferative disorders such as cancer. A wide variety of cancers,including solid tumors, lymphomas and leukemias, are amenable to thecompositions and methods disclosed herein. Types of cancer that may betreated include, but are not limited to: adenocarcinoma of the breast,prostate, and colon; all forms of bronchogenic carcinoma of the lung;myeloid; melanoma; hepatoma; neuroblastoma; papilloma; apudoma;choristoma; branchioma; malignant carcinoid syndrome; carcinoid heartdisease; and carcinoma (e.g., Walker, basal cell, basosquamous,Brown-Pearce, ductal, Ehrlich tumor, Krebs 2, Merkel cell, mucinous,non-small cell lung, oat cell, papillary, scirrhous, bronchiolar,bronchogenic, squamous cell, and transitional cell). Additional types ofcancers that may be treated include: histiocytic disorders; leukemia;histiocytosis malignant; Hodgkin's disease; immunoproliferative small;non-Hodgkin's lymphoma; T-cell lymphoma, B-cell lymphoma, hairy celllymphoma, Burkitt's lymphoma, plasmacytoma; reticuloendotheliosis;melanoma; chondroblastoma; chondroma; chondrosarcoma; fibroma;fibrosarcoma; giant cell tumors; histiocytoma; lipoma; liposarcoma;mesothelioma; myxoma; myxosarcoma; osteoma; osteosarcoma; chordoma;craniopharyngioma; dysgerminoma; hamartoma; mesenchymoma; mesonephroma;myosarcoma; ameloblastoma; cementoma; odontoma; teratoma; thymoma;trophoblastic tumor.

Other cancers that can be treated using the inventive compounds includewithout limitation adenoma; cholangioma; cholesteatoma; cyclindroma;cystadenocarcinoma; cystadenoma; granulosa cell tumor; gynandroblastoma;hepatoma; hidradenoma; islet cell tumor; Leydig cell tumor; papilloma;sertoli cell tumor; theca cell tumor; leimyoma; leiomyosarcoma;myoblastoma; myomma; myosarcoma; rhabdomyoma; rhabdomyosarcoma;ependymoma; ganglioneuroma; glioma; medulloblastoma; meningioma;neurilemmoma; neuroblastoma; neuroepithelioma; neurofibroma; neuroma;paraganglioma; paraganglioma nonchromaffin.

In one embodiment the inventive compounds are candidate therapeuticagents for the treatment of cancers such as angiokeratoma; angiolymphoidhyperplasia with eosinophilia; angioma sclerosing; angiomatosis;glomangioma; hemangioendothelioma; hemangioma; hemangiopericytoma;hemangiosarcoma; lymphangioma; lymphangiomyoma; lymphangiosarcoma;pinealoma; carcinosarcoma; chondrosarcoma; cystosarcoma phyllodes;fibrosarcoma; hemangiosarcoma; leiomyosarcoma; leukosarcoma;liposarcoma; lymphangiosarcoma; myosarcoma; myxosarcoma; ovariancarcinoma; rhabdomyosarcoma; sarcoma; neoplasms; nerofibromatosis; andcervical dysplasia.

In a particular embodiment, the present disclosure provides methods fortreating solid tumor, colon cancer, rectal cancer, colorectal cancer,bladder cancer, gastric cancer, esophageal cancer, head and neck cancer,myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma,glioblastoma, hepatocellular cancers, hepatocellular carcinoma, thyroidcancer, lung cancer, non-small cell lung cancer, a hematological cancer,acute and chronic leukemia, B-cell lymphoma, Waldenström'smacroglobulinemia, T-cell lymphoma, hairy cell lymphoma, diffuse large Bcell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkittlymphoma, pancreatic cancer, melanoma, myeloma, multiple myeloma,pancreatic carcinoma, renal cell carcinoma, renal cancer, cervicalcancer, urothelial cancer, prostate cancer, castration-resistantprostate cancer, ovarian cancer, breast cancer, triple-negative breastcancer, hormone receptor positive breast cancer or HER2+ breast cancer.According to such a method, a therapeutically effective amount of atleast one compound according to Formulae I, II, III, IV, V and VI or astereoisomer, tautomer or pharmaceutically acceptable salt thereof canbe administered to a subject who has been diagnosed with a cellproliferative disease, such as a cancer. Alternatively, a pharmaceuticalcomposition comprising at least one compound according to Formulae I,II, III, IV, V and VI or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof can be administered to a subject who has beendiagnosed with cancer.

In certain embodiments the compounds in accordance with the inventionare administered to a subject with cancer in conjunction with otherconventional cancer therapies such as radiation treatment or surgery.Radiation therapy is well-known in the art and includes X-ray therapies,such as gamma-irradiation, and radiopharmaceutical therapies.

In certain embodiments the inventive eIF4E inhibitor compounds are usedwith at least one anti-cancer agent. Anti-cancer agents includechemotherapeutic drugs. A chemotherapeutic agent includes, but is notlimited to, an inhibitor of chromatin function, a topoisomeraseinhibitor, a microtubule inhibiting drug, a DNA damaging agent, anantimetabolite (such as folate antagonists, pyrimidine analogs, purineanalogs, and sugar-modified analogs), a DNA synthesis inhibitor, a DNAinteractive agent (such as an intercalating agent), and a DNA repairinhibitor.

Illustrative chemotherapeutic agents include, without limitation, thefollowing groups: anti-metabolites/anti-cancer agents, such aspyrimidine analogs (5-fluorouracil, floxuridine, capecitabine,gemcitabine and cytarabine) and purine analogs, folate antagonists andrelated inhibitors (mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine (cladribine)); antiproliferative/antimitoticagents including natural products such as vinca alkaloids (vinblastine,vincristine, and vinorelbine), microtubule disruptors such as taxane(paclitaxel, docetaxel), vincristin, vinblastin, nocodazole, epothilonesand navelbine, epidipodophyllotoxins (etoposide, teniposide), DNAdamaging agents (actinomycin, amsacrine, anthracyclines, bleomycin,busulfan, camptothecin, carboplatin, chlorambucil, cisplatin,cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin,epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan,merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin,procarbazine, taxol, taxotere, temozolamide, teniposide,triethylenethiophosphoramide and etoposide (VP 16)); antibiotics such asdactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin),idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin; enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nitrosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide;hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide,nilutamide) and aromatase inhibitors (letrozole, anastrozole);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory agents; antisecretory agents(breveldin); immunosuppressives (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil);anti-angiogenic compounds (TNP470, genistein) and growth factorinhibitors (vascular endothelial growth factor (VEGF) inhibitors,fibroblast growth factor (FGF) inhibitors); angiotensin receptorblocker; nitric oxide donors; anti-sense oligonucleotides; antibodies(trastuzumab, rituximab); chimeric antigen receptors; cell cycleinhibitors and differentiation inducers (tretinoin); mTOR inhibitors,topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine,camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin,etoposide, idarubicin, irinotecan (CPT-11) and mitoxantrone, topotecan,irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone,methylpednisolone, prednisone, and prenisolone); growth factor signaltransduction kinase inhibitors; mitochondrial dysfunction inducers,toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetellapertussis adenylate cyclase toxin, or diphtheria toxin, and caspaseactivators; and chromatin disruptors.

In certain embodiments, an additional therapeutic agent that may be usedin combination with an eIF4E inhibitor is an inhibitor of animmunosuppression component, which may be an inhibitor of an immunecheckpoint molecule or gene, a metabolic enzyme, an immunosuppressivecytokine, T_(reg) cells, or any combination thereof. As used herein, theterm “immunosuppression component” refers to one or more cells,proteins, molecules, compounds or complexes providing inhibitory signalsto assist in controlling or suppressing an immune response. For example,immunosuppression components include those molecules that partially ortotally block immune stimulation; decrease, prevent or delay immuneactivation; or increase, activate, or up regulate immune suppression.“Controlling or suppressing an immune response,” as used herein, meansreducing any one or more of antigen presentation, T cell activation, Tcell proliferation, T cell effector function, cytokine secretion orproduction, and target cell lysis. Such modulation, control orsuppression can promote or permit the persistence of ahyperproliferative disease or disorder (e.g., cancer, chronicinfections).

Immune checkpoint molecules include immune checkpoint ligands such as,PD-L1, PD-L2, CD80, CD86, B7-H3, B7-H4, HVEM, adenosine, GAL9, VISTA,CEACAM-1, CEACAM-3, CEACAM-5, PVRL2, and immune checkpoint receptorssuch as, PD-1, CTLA-4, BTLA, KIR, LAG3, TIM3, A2aR, CD244/2B4, CD160,TIGIT, LAIR-1, and PVRIG/CD112R). Metabolic enzymes include arginase andindoleamine 2,3-dioxygenase (IDO)), and immunosuppressive cytokinesinclude IL-10, IL-4, IL-1RA, and IL-35. In certain embodiments, aninhibitor of immunosuppression component is a small molecule, anantisense molecule, a ribozyme, an RNAi molecule (e.g., siRNA), anantibody or antigen binding fragment thereof, or fusion polypeptide(e.g., Fc fusion protein).

An antibody specific for PD-1 may be pidilizumab, nivolumab,pembrolizumab, MEDI0680 (formerly AMP-514), AMP-224, or BMS-936558.

An antibody specific for PD-L1 may be MDX-1105 (BMS-936559), durvalumab(formerly MEDI4736), atezolizumab (formerly MPDL3280A), or avelumab(formerly MSB0010718C). A compound specific for PD-L1 may be BMS-1001 orBMS-1166.

A CTLA4 inhibitor may be a CTLA4 specific antibody, such as tremelimumabor ipilimumab, or a CTLA4-Ig fusion protein (e.g., abatacept,belatacept).

A LAG3 inhibitor may be LAG525, IMP321, IMP701, 9H12, or BMS-986016.

An IDO inhibitor may be levo-1-methyl tryptophan, epacadostat(INCB024360; Liu et al., Blood 115:3520-30, 2010), ebselen (Terentis etal., Biochem. 49:591-600, 2010), indoximod, NLG919 (Mautino et al.,American Association for Cancer Research 104th Annual Meeting 2013; Apr.6-10, 2013), 1-methyl-tryptophan (1-MT)-tira-pazamine, or anycombination thereof.

In certain embodiments an eIF4E inhibitor in accordance with the presentinvention is used simultaneously, in the same formulation or in separateformulations, or sequentially with an additional agent(s) as part of acombination therapy regimen.

eIF4E inhibitors according to Formulae I, II, III, IV, V and VIincluding their corresponding salts and pharmaceutically acceptablecompositions of Formulae I, II, III, IV, V and VI compounds are alsoeffective as therapeutic agents for treating or preventing cytokinemediated disorders, such as inflammation in a patient, preferably in ahuman. In one embodiment, a compound or composition in accordance withthe invention is particularly useful for treating or preventing adisease selected from chronic or acute inflammation, chronicinflammatory arthritis, rheumatoid arthritis, psoriasis, COPD,inflammatory bowel disease, septic shock, Crohn's disease, ulcerativecolitis, multiple sclerosis and asthma.

The inventive compounds their corresponding salts and pharmaceuticallyacceptable compositions are candidate therapeutics for treating brainrelated disorders which include without limitation autism, FragileX-syndrome, Parkinson's disease and Alzheimer's disease. Treatment iseffected by administering to a subject in need of treatment a compoundof Formulae I, II, III, IV, V and VI, its pharmaceutically acceptablesalt form, or a pharmaceutically acceptable composition of a compound ofFormulae I, II, III, IV, V and VI or its salt.

The invention also supports the use of the inventive compounds or apharmaceutically acceptable formulation of the inventive compound as aninhibitor of eIF4E activity. Such inhibition is achieved by contacting acell expressing eIF4E with a compound or a pharmaceutically acceptableformulation, to lower or inhibit eIF4E activity, to provide therapeuticefficacy for a eIF4E dependent condition in a mammal in need thereof.

Therapeutically effective dosages of a compound according to Formulae I,II, III, IV, V and VI or a composition containing a compound of FormulaeI, II, III, IV, V and VI will generally range from about 1 to 2000mg/day, from about 10 to about 1000 mg/day, from about 10 to about 500mg/day, from about 10 to about 250 mg/day, from about 10 to about 100mg/day, or from about 10 to about 50 mg/day. The therapeuticallyeffective dosages may be administered in one or multiple doses. It willbe appreciated, however, that specific doses of the compounds of theinvention for any particular patient will depend on a variety of factorssuch as age, sex, body weight, general health condition, diet,individual response of the patient to be treated, time ofadministration, severity of the disease to be treated, the activity ofparticular compound applied, dosage form, mode of application andconcomitant medication. The therapeutically effective amount for a givensituation will readily be determined by routine experimentation and iswithin the skills and judgment of the ordinary clinician or physician.In any case the compound or composition will be administered at dosagesand in a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

General Methods for Synthesizing Compounds

Compounds described in this disclosure have a left-hand side and aright-hand side, illustrated below for Formula (II):

In general, the compounds described in this disclosure can besynthesized by constructing the left-hand side and the right-hand andcoupling the two sides together, as described in the general methodsbelow. Many of the reactions carried out on the left-hand side prior tocoupling, such as cyanation, can be postponed until the coupling iscompleted. Similarly, some of the reactions listed as post-couplingprotocols can be performed prior to the coupling reaction to give thesame result.

Example 1. General Methods for Synthesizing 7-Aza-Thienylpyridine andDerivative Compounds

The 7-aza-thienylpyridine compounds in Table 1 can be synthesized usingmethods described in Example 1. For some compounds, some of thereactions described in Example 2 and/or Example 3, below, can be used toprepare the compounds.

Example 1A. Methods of Synthesizing the Left-Hand Side Example 1A.1

To dry N-isopropylpropan-2-amine (1.2 equiv.) in THF (0.3 M) at 0° C. isadded n-butyllithium (2.5 M in hexane) (1.2 equiv.) slowly and themixture is stirred for 10 min. The LDA solution in THF is used directly.To a solution of 3-bromo-2-chloro-5-fluoro-pyridine (A, 1 equiv.) in THF(0.3 M) at −78° C. is added the LDA solution and the resulting darkmixture is stirred for 45 min. Chloro(trimethyl)silane (1.7 equiv.) isadded and the mixture is allowed to warm to rt within ca. 15 h. Thereaction mixture is quenched with water, the layers separated, and theaqueous layer extracted with ethylacetate. The organic layers arecombined, evaporated with silica gel and the free-flowing silica gel isloaded on a column and(3-bromo-2-chloro-5-fluoro-6-methyl-4-pyridyl)-trimethyl-silane (B) ispurified by silica gel chromatography.

To a solution of (3-bromo-2-chloro-5-fluoro-4-pyridyl)-trimethyl-silane(B, 1 equiv.) in THF (0.25 M) at −78° C. is added LDA solution (1.2equiv.) prepared as above and the resulting dark mixture is stirred for45 min. Iodomethane (10 equiv.) is added and the mixture is allowed towarm to rt within ca. 15 h. The reaction mixture is quenched with water,the layers separated, and the aqueous layer further extracted withethylacetate. The organic layers are combined, evaporated with silicagel and the free-flowing silica gel loaded on a column and(3-bromo-2-chloro-5-fluoro-6-methyl-4-pyridyl)-trimethyl-silane (C) ispurified via silica gel chromatography.

(3-bromo-2-chloro-5-fluoro-6-methyl-4-pyridyl)-trimethyl-silane (C, 1equiv.) is dissolved in THF (0.67 M), cooled to 0° C., andtetrabutylammonium fluoride (in THF) (1.2 equiv.) is added and themixture stirred at 0° C. After 10 min the reaction is quenched withNH₄Cl(aq) and diluted with EtOAc. The organic phase is washed with watertwice, dried, filtered, concentrated, and loaded on a column and3-bromo-2-chloro-5-fluoro-6-methylpyridine (D) is purified via silicagel chromatography.

Example 1A.2

To a solution of 3-bromo-2-chloro-5-fluoro-6-methylpyridine (A, 1equiv.) in tetrahydrofuran (0.40 M) at −96° C. (internal temperature),lithium diisopropylamide solution (1.2 equiv.; 2 M in tetrahydrofuran)is added over a period of 60 min, maintaining internal temperaturebetween −96 to −84° C. and the reaction mixture is maintained at −96 to−90° C. for 2 h. Carbon dioxide gas is purged into the reaction mixturefor 35 minutes, maintaining internal temperature at −95 to −78° C.Progress of the reaction is monitored by TLC and the reaction mixture iswarmed to −50 to −45° C., quenched with saturated aqueous ammoniumchloride solution, and stirred for 10 min. The solution is acidified topH 2.0-1.5 with 6 N hydrochloric acid, diluted with ethyl acetate andthe organic layer washed with water. The aqueous layer is extracted withethyl acetate and the combined organic layers are concentrated underreduced pressure, stirred in dichloromethane and the solid precipitatedis filtered, washed with dichloromethane, and dried under vacuum toafford 3-bromo-2-chloro-5-fluoro-6-methylisonicotinic acid (B).

To a solution of 3-bromo-2-chloro-5-fluoro-6-methylisonicotinic acid (B,1 equiv.) in N,N-dimethylformamide (0.32 M), acetamidine hydrochloride(C, 1.4 equiv.) is added and reaction mixture is cooled at 0° C.N,N-di-isopropylethylamine (5 equiv.) and HATU (1.1 equiv.) are addedand reaction mixture is stirred at room temperature for 1 h. Thereaction mixture is diluted with water, extracted with ethyl acetate andthe combined organic layers are dried over anhydrous sodium sulphate,filtered and concentrated to afford3-bromo-2-chloro-5-fluoro-N-(1-iminoethyl)-6-methylisonicotinamide (D).

To a stirred solution of3-bromo-2-chloro-5-fluoro-N-(1-iminoethyl)-6-methylisonicotinamide (D, 1equiv.) in tetrahydrofuran (2 M), sodium hydride (60%) (1 equiv.) isadded at 0° C. and stirred for 1 h at 0° C. The reaction mass is slowlywarmed to room temperature and stirred for 16 h. The reaction mass iscooled to 0° C., acidified with 2 N hydrochloric acid (pH ˜2), and theresulting solid filtered, washed with 10% methanol in diethyl ether anddried to afford5-bromo-6-chloro-2,8-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one (E).

To a stirred solution of5-bromo-6-chloro-2,8-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one (E, 1equiv.) in N,N-dimethylformamide (0.056 M), copper(I) cyanide (1.2equiv.) is added at room temperature. The reaction is heated to 100° C.and stirred for 16 h. The reaction is quenched with 1 N hydrochloricacid, and the solid is filtered, washed with diethyl ether, and purifiedby via chromatography to afford6-chloro-2,8-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(F).

5-bromo-6-chloro-2,8-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one (E, 1equiv.), copper(I) cyanide (1.2 equiv.), and NMP (0.072 M) are combinedin a sealable vessel with a stir bar. The resulting mixture is sealed,stirred, and heated at 90° C. for 20 h. Upon cooling to roomtemperature, the reaction mixture is diluted with 1% TFA inacetonitrile, filtered, and purified via chromatography to afford6-chloro-2,8-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(F).

To a solution of5-bromo-6-chloro-2,8-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one (E, 1equiv.) in N,N-dimethylacetoamide (0.07 M) is added dicyanozinc (1.4equiv.) and tetrakis(triphenylphosphine)palladium (2.0 equiv.) at roomtemperature. The mixture is degassed with argon for 5 min, and stirredfor 5 h at 130° C. Upon cooling to room temperature, the mixture isdiluted with dimethyl sulfoxide and acetonitrile and purified bychromatography to afford6-chloro-2,8-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(F).

Example 1A.3

A solution of6-chloro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(A, 1 equiv.) in dimethyl sulfoxide (0.23 M) is purged with argon gasfor 10 minutes. 18-Crown-6 ether (1.5 equiv.) and potassium fluoride (5equiv.) are added to the reaction mixture and purging is continued for 5minutes and stirred in a preheated oil bath at 160° C. for 2 h. Thereaction mixture is cooled, poured on to ice cold water, extracted withethyl acetate, and the ethyl acetate layer washed with brine solution,dried over anhydrous sodium sulphate, concentrated, and triturated withdiethyl ether to get6-fluoro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(B).

Example 1A.4

To a solution of tert-butyl methyl(piperidin-4-yl)carbamate (A, 1equiv.) and N,N-diisopropylethylamine (10 equiv.) in acetonitrile (0.35M), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2, 1.25 equiv.) isadded dropwise and the mixture stirred at room temperature for 16 h. Thereaction mixture is diluted with water, extracted with dichloromethane,and the organic layer dried over anhydrous sodium sulphate, filtered,concentrated, and purified by flash column chromatography to affordtert-butyl methyl(1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamate (C).

A solution of tert-butylmethyl(1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamate (C, 1 equiv.) inhydrochloride (4 M solution in 1,4-dioxane, 0.34 M) is stirred at roomtemperature for 4 h. The reaction mixture is concentrated to affordN-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride (D).

A solution of6-chloro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(E, 1 equiv.) and N-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-aminehydrochloride (D, 3 equiv.) in N,N-dimethylacetamide (0.24 M), potassiumfluoride (8 equiv.) and 18-crown-6 (1 equiv.) are added and the reactionmixture heated at 130° C. for 16 h. The reaction mixture is cooled,diluted with water, extracted with ethyl acetate, and the organic layerwashed with water, dried over anhydrous sodium sulphate, filtered,concentrated, and purified by flash column chromatography to afford2-methyl-6-(methyl(1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(F).

Example 1A.5

1,4-Dioxane (24 mL) and water (8 mL) is added to a mixture of2,3-dibromo-5-fluoropyridine (A, 3000 mg, 11.8 mmol), cyclopropylboronicacid (1112 mg, 12.9 mmol), and cesium carbonate (8436 mg, 25.9 mmol).The mixture is bobbled with argon bubbling for 5 min.Tetrakis(triphenylphosphine)palladium (680 mg, 0.590 mmol) is added tothe mixture, and the mixture is vacuumed and backfilled with argon threetimes. The resulting clear yellow reaction mixture is stirred for 72 hat 110° C. The mixture is diluted with ethyl acetate, and washed withbrine, dried over anhydrous magnesium sulfate, and concentrated in vacuoafter filtration. Purification by silica gel column chromatography (0 to5% ethyl acetate in hexane) gave 3-bromo-2-cyclopropyl-5-fluoropyridine(B).

n-Butyllithium (2.5 M in hexane, 2.1 mL, 5.30 mmol) is added to astirred solution of diisopropylamine (0.81 mL, 5.80 mmol) in THF (5 mL)at 0° C. under argon. The resulting light yellow solution is stirred for10 min at 0° C. and then added slowly to a stirred solution of3-bromo-2-cyclopropyl-5-fluoropyridine (B, 1000 mg, 4.60 mmol) intetrahydrofuran (20 mL) at −78° C. under argon. The resulting yellowreaction mixture is stirred at −78° C. under argon for 30 min and thencarbon dioxide gas is bubbled in for 2 min. The mixture is stirred at−78° C. for 10 min and then warmed to room temperature over 5 min. Thereaction is diluted with 0.1 N sodium hydroxide, and extracted withdiethyl ether. Water layer is acidified by 3 M hydrogen chloride, andextracted with ethyl acetate twice, dried over anhydrous magnesiumsulfate, and concentrated in vacuo after filtration to afford3-bromo-2-cyclopropyl-5-fluoroisonicotinic acid (C).

To a N,N-dimethylformamide (14 mL) solution of3-bromo-2-cyclopropyl-5-fluoroisonicotinic acid (C, 730 .mg, 2.81 mmol)is added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (1387 mg, 3.60 mmol) andN,N-diisopropylethylamine (2.0 mL, 11.2 mmol) at 0° C. The mixture isstirred for 5 min at room temperature, and acetamidine hydrochloride (D,345 mg, 3.60 mmol) is added to the mixture. After stirring the mixturefor 17 h at room temperature, ice-cold water is added to the mixture,and extracted with ethyl acetate twice. The combined extracts are washedwith aqueous solution of ammonium chloride, aqueous solution of sodiumbicarbonate, and brine, dried over anhydrous magnesium sulfate, andconcentrated in vacuo after filtration. The residue is dissolvedtetrahydrofuran (18 mL), and sodium hydride (60% in mineral oil, 225 mg,5.60 mmol) is added to the mixture at 0° C. After stirring the mixturefor 18 h, ice-cold water is added to the mixture, and extracted withethyl acetate three times, dried over anhydrous magnesium sulfate, andconcentrated in vacuo after filtration. The residue is triturated withdichloromethane, and filtered to afford5-bromo-6-cyclopropyl-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (E).

Example 1A.6

To a solution of ethyl 3-amino-6-chloro-5-cyano-2-methylisonicotinate(A, 0.90 g, 3.75 mmol) in 1,4-dioxane and water (4:1, 10.0 mL),phenylboronic acid (B, 0.68 g, 5.62 mmol) and potassium carbonate (1.53g 11.25 mmol) are added. The reaction mixture is purged with argon for 5min. Then, [1,1-bis(diphenylphospino)ferrocene] dichloropaladium(II)(complex with dichloromethane, 0.031 g, 0.037 mmol) is added and thereaction mixture is heated at 90° C. for 5 h. After this time, thereaction mixture is cooled, diluted with water, and extracted with ethylacetate. The organic layer is dried over anhydrous sodium sulfate,filtered, and concentrated to obtain the crude product. This is purifiedby silica gel (100-200 mesh) column chromatography using 30-40% ethylacetate in hexane to afford ethyl3-amino-5-cyano-2-methyl-6-phenylisonicotinate (C).

To a solution of ethyl 3-amino-5-cyano-2-methyl-6-phenylisonicotinate(C, 0.6 g, 2.13 mmol) in tetrahydrofuran and water (4:1, 6 mL) at roomtemperature, lithium hydroxide (0.44 g, 10.67 mmol) is added. Thisreaction mixture is stirred at room temperature for 2 h. After thistime, the reaction mixture is diluted with water, acidified with 1 Nhydrochloric acid, and extracted with ethyl acetate. The organic layeris dried over anhydrous sodium sulfate, filtered, and concentrated toobtain the crude product. This is washed with diethyl ether to afford3-amino-5-cyano-2-methyl-6-phenylisonicotinic acid (D).

To a solution of 3-amino-5-cyano-2-methyl-6-phenylisonicotinic acid (D,0.5 g, 1.97 mmol) in N,N-dimethylformamide (5.0 mL), ammonium chloride(0.31 g, 5.92 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.840 g, 2.21 mmol) are added. This reactionmixture is cooled to 0° C., N,N-di-isopropylethylamine (2.7 mL, 14.70mmol) is added, and the reaction mixture is stirred at 0° C. for 10 min.Then, the reaction mixture is diluted with water and extracted withethyl acetate. The organic layer is dried over anhydrous sodium sulfate,filtered, and concentrated to obtain the crude product. This is purifiedby silica gel (100-200 mesh) column chromatography using 30-40% ethylacetate in hexanes to afford3-amino-5-cyano-2-methyl-6-phenylisonicotinamide (E).

A solution of 3-amino-5-cyano-2-methyl-6-phenylisonicotinamide (E, 0.4g, 1.19 mmol), in triethylorthoacetate and acetic acid (4:1, 4 mL) isheated at 130° C. for 2 h under microwave. After this time, the reactionmixture is cooled, diluted with hexanes, and filtered to afford2,8-dimethyl-4-oxo-6-phenyl-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(F).

Example 1A.7

To a stirred mixture of 3-chloro-5-fluoroisonicotinic acid (A, 1 equiv.)in diethyl carbonate (0.29 M) and water (0.44 M) under argon is addedsodium 4,4-difluorocyclohexane-1-sulfinate (B, 3 equiv.) and the mixtureis cooled to 0° C. tert-Butyl hydroperoxide (70 wt. % in water) (10equiv.) is added and the mixture is stirred for 5 min then heated at 90°C. under argon with an oil bath for 3 h. Volatiles are removed on arotary evaporator. The residue is taken up in a mixture of water,acetonitrile and TFA, filtered, and purified via preparatory HPLC toafford a mixture of3-chloro-2-(4,4-difluorocyclohexyl)-5-fluoroisonicotinic acid (C) and5-chloro-2-(4,4-difluorocyclohexyl)-3-fluoroisonicotinic acid (D).

HATU (1.1 equiv.) is added to a stirred solution of3-chloro-2-(4,4-difluorocyclohexyl)-5-fluoroisonicotinic acid (C) and5-chloro-2-(4,4-difluorocyclohexyl)-3-fluoroisonicotinic acid (D 1equiv.) in DMF (0.46 M) at room temperature under argon. After 2 minN,N-diisopropylethylamine (1.1 equiv.) is added. After stirring at roomtemperature for 35 min a solution of acetamidine hydrochloride (2equiv.) and N,N-diisopropylethylamine (2.2 equiv.) in DMF (5.6 M) (thisis heated with a heat gun and sonicated to get all of the acetamidinedissolved) is added. The resulting solution is stirred vigorously atroom temperature under argon for 1.5 h. The reaction mixture is dilutedwith ethyl acetate and washed three times with brine. The organics aredried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and dried under high vacuum to afford a viscous amber oil.The oil is dissolved in THF (0.046 M) with stirring under argon. Sodiumhydride (2.2 equiv.) is added and the reaction mixture is stirredvigorously at room temperature under argon for 21 h. A solution ofammonium chloride (5 equiv.) in water (0.14 M) is added with vigorousstirring. The resulting mixture is partitioned between ethyl acetate andbrine. The organics are dried over magnesium sulfate, filtered, andconcentrated on a rotary evaporator. The residue is taken up in NMP,acetonitrile, and TFA, filtered, and purified via preparatory HPLC toafford5-chloro-6-(4,4-difluorocyclohexyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(E) and5-chloro-8-(4,4-difluorocyclohexyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(F)

Example 1A.8

4-Methoxybenzyl chloride (1.27 mL, 9.38 mmol) is added to a stirredmixture of 5-bromo-6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (A,1.98 g, 7.21 mmol) and cesium carbonate (3.29 g, 10.1 mmol) in DMA (14mL) at room temperature under argon. The resulting mixture is stirredvigorously and heated at 50° C. under argon for 2 h. The reactionmixture is diluted with ethyl acetate (1.5 L), washed once with water,and twice with brine. The organics are dried over magnesium sulfate,filtered, concentrated on a rotary evaporator with silica gel, andpurified via silica gel chromatography (0-40% ethyl acetate indichloromethane) to afford5-bromo-6-chloro-3-(4-methoxybenzyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(B).

5-Bromo-6-chloro-3-(4-methoxybenzyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(B, 1.24 g, 3.14 mmol) is dissolved in DMF (20 mL) with stirring at 90°C. under argon. Copper(I) cyanide (338 mg, 3.77 mmol) is added and theresulting clear red solution is stirred and heated at 90° C. under argonfor 1 h 40 min. While still hot the reaction mixture is diluted withethyl acetate and filtered through Celite into ethyl acetate (600 mL).The filter cake is washed with ethyl acetate. The filtrate is shakenwith water to give an emulsion which is filtered. The filtrate ispartitioned between ethyl acetate and brine. The organics are washedtwice with brine, dried over magnesium sulfate, filtered, concentratedon a rotary evaporator with silica gel, and purified via silica gelchromatography (0-100% ethyl acetate in dichloromethane) to afford6-chloro-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(C).

6-Chloro-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(C, 100 mg, 0.293 mmol), 1-(2-fluoroethyl)piperazine bis HCl salt (D,120 mg, 0.587 mmol), potassium carbonate (183 mg, 1.32 mmol), and NMP(1.5 mL) are combined in a sealable vessel with a stir bar. Theresulting mixture is sealed, stirred vigorously, and heated at 70° C.with an oil bath for 40 min. N,N-diisopropylethylamine (0.26 mL, 1.47mmol) is added and the resulting mixture is sealed, stirred vigorously,and heated at 100° C. with an oil bath for 1 h. After cooling to roomtemperature, the reaction mixture is diluted with methanol and aceticacid (0.34 mL, 5.87 mmol). The resulting mixture is filtered andpurified via preparatory HPLC (10-45% acetonitrile in water with 0.1%TFA). Fractions containing the desired product are combined andconcentrated on a rotary evaporator down to ˜20 mL and then lyophilizedto dryness to afford a yellow oil. The oil is dissolved in acetonitrileand loaded onto a 2-gram Strata X-C ion exchange column from Phenomenex.The column is washed sequentially with water, acetonitrile, methanol,and then 5% ammonium hydroxide in methanol. Eluent containing thedesired product is concentrated on a rotary evaporator and dried underhigh vacuum to afford6-(4-(2-fluoroethyl)piperazin-1-yl)-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(E).

To a stirred mixture of6-(4-(2-fluoroethyl)piperazin-1-yl)-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(E, 28.2 mg, 0.065 mmol) in diethyl carbonate (0.4 mL) and water (0.2mL) under argon is added bis((isopropylsulfinyl)oxy)zinc (F, 54.2 mg,0.194 mmol) followed by tert-butyl hydroperoxide (70 wt. % in water)(0.092 mL, 0.666 mmol). The mixture is stirred and heated at 90° C.under argon with an oil bath for 10 min. The reaction mixture is dilutedwith NMP, acetic acid, and methanol, filtered, and purified viapreparatory HPLC (15-65% acetonitrile in water with 0.1% TFA). Fractionscontaining the desired product are loaded onto a Strata X-C ion exchangecolumn from Phenomenex. The column is washed sequentially with water,acetonitrile, methanol, and then 5% ammonium hydroxide in methanol.Eluent containing the desired product is concentrated on a rotaryevaporator and dried under high vacuum to afford6-(4-(2-fluoroethyl)piperazin-1-yl)-8-isopropyl-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(G).

6-(4-(2-Fluoroethyl)piperazin-1-yl)-8-isopropyl-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(G, 23.8 mg, 0.050 mmol), TFA (2 mL), and water (0.1 mL) are combined ina sealable vessel with a stir bar, sealed, stirred, and heated at 70° C.for 1 h. Volatiles are removed on a rotary evaporator. The residue istaken up in NMP and methanol, filtered, and purified via preparatoryHPLC (10-40% acetonitrile in water with 0.1% TFA). Fractions containingthe desired product are loaded onto a Strata X-C ion exchange columnfrom Phenomenex. The column is washed sequentially with water,acetonitrile, methanol, and then 5% ammonium hydroxide in methanol.Eluent containing the desired product is concentrated on a rotaryevaporator and dried under high vacuum to afford6-(4-(2-fluoroethyl)piperazin-1-yl)-8-isopropyl-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(H).

Example 1A.9

To a 1,4-dioxane (5.6 mL) solution of6-chloro-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(A, 192 mg, 0.560 mmol) is added 1-(2,2,2-trifluoroethyl)piperidin-4-ol(B, 206 mg, 1.13 mmol), cesium carbonate (367 mg, 1.13 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (105 mg, 0.169 mmol), andtris(dibenzylideneacetone)dipalladium (103 mg, 0.113 mmol) at roomtemperature. The mixture is bubbled with argon for 5 min, and stirredfor 2 h at 100° C. The mixture is diluted with ethyl acetate andfiltered through a pad of Celite. The filtrate is concentrated in vacuo.Purification by silica gel column chromatography (0-80% ethyl acetate inhexane) gave crude3-(4-methoxybenzyl)-2-methyl-4-oxo-6-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(C).

Example 1A.10

To a 1,4-dioxane (3.9 mL) solution of6-chloro-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(1, 134 mg, 0.390 mmol) is added phenylmethanethiol (1a, 0.09 mL, 0.790mmol), cesium carbonate (256 mg, 0.790 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (73 mg, 0.118 mmol), andtris(dibenzylideneacetone)dipalladium (72 mg, 0.0790 mmol) at roomtemperature. The mixture is bubbled with argon for 5 min, and stirredfor 2 h at 100° C. The mixture is diluted with ethyl acetate, and washedwith 5% breech in water, dried over anhydrous magnesium sulfate, andconcentrated in vacuo after filtration. Purification by preparative HPLC(Cis column, 15-85% acetonitrile in water+0.1% trifluoroacetic acid)gave6-(benzylthio)-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(2).

To a dichloromethane (2 mL) and water (0.4 mL) solution of6-(benzylthio)-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(2, 74 mg, 0.173 mmol) is added sulfuryl chloride (0.1 mL, 1.21 mmol) at0° C. The mixture is stirred for 1 h at room temperature. Organic layeris separated and dried over anhydrous magnesium sulfate, andconcentrated in vacuo after filtration to give crude5-cyano-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-6-sulfonylchloride (3).

To a dichloromethane (1.7 mL) solution of5-cyano-3-(4-methoxybenzyl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-6-sulfonylchloride (3, 70 mg, 0.173 mmol) is added 1-methylpiperazine (0.06 mL,0.520 mmol) and diisopropylethylamine (0.09 mL, 0.520 mmol) at 0° C.After stirring the mixture for 1 h at room temperature, the mixture isdiluted with aqueous sodium bicarbonate. Organic materials are extractedwith ethyl acetate twice, dried over anhydrous magnesium sulfate, andconcentrated in vacuo after filtration. Purification by preparative HPLC(Cis column, 15-60% acetonitrile in water+0.1% trifluoroacetic acid)gave3-(4-methoxybenzyl)-2-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(4).

Example 1A.11

A solution of 5-bromo-2-chloro-3-fluoropyridine (1, 30.0 g, 143.6 mmol)in tetrahydrofuran (300 mL) is cooled to −78° C. andlithiumdisopropylamide (2 M in THF, 78.9 mL, 157.9 mmol) is addeddropwise. This reaction mixture is stirred at −78° C. for 1 h. Then, thereaction mixture is purged with carbon dioxide gas for 15 min allowed towarm at room temperature. The reaction mixture is quenched with ammoniumchloride solution and diluted with water. The aqueous layer is washedwith ethyl acetate, acidified with 6 N hydrochloric acid solution, andextracted with 15% methanol in dichloromethane. The organic layer isdried over anhydrous sodium sulfate, filtered, and concentrated toafford 5-bromo-2-chloro-3-fluoroisonicotinic acid (2).

To solution of 5-bromo-2-chloro-3-fluoroisonicotinic acid (2, 18.0 g,71.1 mmol) in N,N-dimethylformamide (30 mL) at 0° C., acetamidinehydrochloride (2a, 13.4 g, 142.3 mmol) is added. ThenN,N-diisopropylethylamine (110 mL, 711.0 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (40.5 g, 106.6 mmol) are added and thereaction mixture is stirred at room temperature for 2 h. After thistime, reaction mixture is diluted with water and extracted with ethylacetate. The organic layer is dried over anhydrous sodium sulfate,filtered, and concentrated to afford crude5-bromo-2-chloro-3-fluoro-N-(1-iminoethyl)isonicotinamide (3).

A solution of crude5-bromo-2-chloro-3-fluoro-N-(1-iminoethyl)isonicotinamide (3, 18.0 g) intetrahydrofuran (200 mL) is cooled to 0° C., then 60% sodium hydride inmineral oil (7.30 g NaH, 184.3 mmol) is added portionwise and thereaction mixture is stirred at room temperature for 12 h. After thistime, the reaction mixture is poured into ice-cold water. The aqueouslayer is washed with 5% methanol in dichloromethane, acidified with 6 Nhydrochloric acid solution, and extracted with 10% methanol indichloromethane. The organic layer from this extraction is dried overanhydrous sodium sulfate, filtered, and concentrated to obtain the crudeproduct which is washed with diethyl ether to afford5-bromo-8-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (4).

To a solution of5-bromo-8-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (4, 8.0 g,29.3 mmol) in N,N-dimethylformamide (80.0 mL), copper(I) cyanide (4.1 g,46.8 mmol) is added. The reaction mixture is heated at 90° C. for 3 h.After this time, the reaction mixture is cooled, diluted with water,acidified with 6 N hydrochloric acid solution, and extracted with ethylacetate. The organic layer is concentrated to obtain the crude productwhich is purified by silica gel (100-200 mesh) column chromatographyusing 40-50% ethyl acetate in hexanes as eluent to afford8-chloro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(5).

To a solution of8-chloro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(5, 1.0 g, 4.55 mmol) in 1,4-dioxane (15.0 mL) at room temperature,2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (5a, 1.0 mL, 7.5 mmol),potassium carbonate (2.0 g, 15.0 mmol), and water (2 mL) are added. Thisreaction mixture is degassed with nitrogen for 10 min. Then,[1,1-bis(diphenylphospino)ferrocene] dichloropaladium(II), complex withdichloromethane (0.183 g, 0.225 mmol) is added and reaction mixture isheated at 95° C. for 12 h. After this time, the reaction mixture iscooled and concentrated under reduced pressure to obtain the crudeproduct which is purified by silica gel (100-200 mesh) columnchromatography using 10% methanol in dichloromethane as eluent to afford2,8-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(6).

Example 1A.12

Diethylaminosulfur trifluoride (1.44 mL, 10.4 mmol) is added to astirred solution of 5-bromo-3-fluoropicolinaldehyde (1, 0.97 g, 4.75mmol) in DCM (20 mL) at −78° C. under argon. The cold bath is removed,and the reaction mixture is allowed to warm to room temperature underargon for 1.5 h. The reaction mixture is poured into a stirred mixtureof saturated aqueous sodium bicarbonate and ice. The resulting mixtureis stirred vigorously at room temperature for 1 h to fully quench thereaction mixture. The phases are separated, and the aqueous phaseextracted with dichloromethane. The combined organics are dried oversodium sulfate, filtered, concentrated on a rotary evaporator, andpurified via silica gel chromatography (0-10% ethyl acetate in hexanes)Fractions containing the desired product are combined and concentratedon a rotary evaporator at room temperature. The residue is diluted withdry THF (5 mL) and concentrated on a rotary evaporator. The residue isdried under high vacuum for 2 min to afford5-bromo-2-(difluoromethyl)-3-fluoropyridine (2).

Example 1A.13

A solution of 3-fluoropyridin-2-ol (1, 20.0 g, 176.9 mmol) inN,N-dimethylformamide (220.0 mL) is cooled at 0° C., bromine (10.30 mL,194.6 mmol) is added drop wise and reaction mixture is stirred at 0° C.for 2 h. After completion reaction mixture is diluted with water andextracted with ethyl acetate. The organic layer is washed with sodiumbicarbonate and brine, dried over anhydrous sodium sulphate, filteredand concentrated to get crude compound. Crude compound is purified bycolumn chromatography using silica gel (100-200 mesh) and 2-3% methanolin dichloromethane to afford 5-bromo-3-fluoropyridin-2-ol (2).

To a solution of 5-bromo-3-fluoropyridin-2-ol (2, 11.0 g, 57.29 mmol) inN,N-dimethylformamide (110 mL), cesium carbonate (24.59 g 74.47 mmol)and sodium 2-bromo-2,2-difluoroacetate (17.04 g, 85.93 mmol) are addedand reaction mixture is heated at 55° C. After completion, reactionmixture is diluted with water and extracted with diethyl ether. Theorganic layer is dried over anhydrous sodium sulphate, filtered andconcentrated to get crude compound. Crude compound obtained isconcentrated under reduced pressure to obtain crude product which ispurified by column chromatography using silica gel (100-200 mesh) and1-2% ethyl acetate in hexane to afford5-bromo-2-(difluoromethoxy)-3-fluoropyridine (3).

Example 1A.14

To a solution of2,8-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile (1,0.16 g, 0.8 mmol) and zinc difluoromethanesulpfinate (0.472 g, 1.6 mmol)in a mixture of dichloromethane and water (4:1, 2 mL),trifluoroaceticacid (0.06 mL, 0.8 mmol) and tert-butyl hydroperoxide(0.23 mL, 2.4 mmol) are added. This mixture is stirred at roomtemperature for 16 h. After this time, the reaction mixture isconcentrated under reduced pressure, diluted with water, and extractedwith dichloromethane. The combined organic layer is washed with waterand then brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude product is purified by silica gel (100-200 mesh)flash chromatography using 40% ethyl acetate in hexanes as eluent. Thedesired fractions are concentrated under reduced pressure to afford6-(difluoromethyl)-2,8-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(2).

Example 1A.15

A solution of2,8-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile (1,0.200 g, 0.99 mmol) and bis(((trifluoromethyl)sulfinyl)oxy)zinc (1a,0.662 g 1.99 mmol) is stirred in chloroform (2.0 mL) and water (2.0 mL),tert-butyl hydrogen peroxide (70%) (0.38 mL, 2.99 mmol) is added at 0°C. The reaction mixture is stirred at room temperature for 15 h. Afterthis time, the reaction mixture is diluted water and extracted withethyl acetate. The organic layer is dried over anhydrous sodium sulfate,filtered, and concentrated to obtain the crude product. The crude ispurified by silica gel (100-200 mesh) column chromatography using 70-80%ethyl acetate in hexanes as eluent. The desired fractions areconcentrated under reduced pressure to afford2,8-dimethyl-4-oxo-6-(trifluoromethyl)-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(2).

Example 1A.16

To a solution of6-chloro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(1, 1.0 g, 4.54 mmol), in dichloromethane:water (1:1) (20.0 mL) is added2,2,2-trifluoroacetic acid (10.4 mL, 13.63 mmol). Reaction mixture isstirred at room temperature for 15 min before the addition ofphenylboronic acid (1a, 1.65 g, 13.63 mmol) and stirred for 40 min.Silver nitrate (0.154 g, 0.90 mmol) and Potassium persulfate (2.45 g,9.09 mmol). is added and reaction mixture is stirred for 24 h at roomtemperature. After completion, reaction mixture is diluted with waterand extracted with dichloromethane. The organic layer is dried overanhydrous sodium sulphate, filtered and concentrated to get crudecompound. The crude is washed with 30% diethyl ether in pentene toafford6-chloro-2-methyl-4-oxo-8-phenyl-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(2).

Example 1A.17

Zinc powder (<10 micron) (37.7 mg, 0.58 mmol) is weighed out in a dry 1dram vial and placed under argon. DMA (0.4 mL) is added followed byiodine (3.6 mg, 0.014 mmol). The resulting mixture is stirred vigorouslyat room temperature under argon until the red color of iodine faded (5min). 4-(bromomethyl)tetrahydro-2H-pyran (2a, 0.072 mL, 0.56 mmol) isadded and the resulting mixture is sealed, stirred vigorously, andheated at 80° C. for 23 h. After cooling to room temperature thereaction mixture is placed under argon and6-chloro-3-(4-methoxybenzyl)-2,8-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(2, 49.9 mg, 0.14 mmol) and bis(triphenylphosphine)nickel(II) dichloride(9.2 mg, 0.014 mmol) are added. The resulting mixture is stirredvigorously at room temperature under argon for 2.5 h and then at 50° C.for 2 h. The reaction mixture is diluted with NMP and methanol,filtered, and purified via preparatory HPLC (15-70% acetonitrile inwater with 0.1% TFA). Fractions containing the desired product arecombined and lyophilized to dryness to afford3-(4-methoxybenzyl)-2,8-dimethyl-4-oxo-6-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(3).

Example 1A.18

2,3-Dibromo-5-fluoropyridine (1, 3.15 g, 12.4 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1a, 1.93 mL, 13.6mmol), cesium carbonate (8.86 g, 27.2 mmol), 1,4-dioxane (24 mL) andwater (6 mL) are combined in a 100 mL round bottom flask with a stirbar.The atmosphere in the flask is removed under vacuum and replaced withargon twice. Tetrakis(triphenylphosphine)palladium(0) (0.71 g, 0.62mmol) is added and the atmosphere in the flask is removed under vacuumand replaced with argon twice. The resulting clear yellow reactionmixture is stirred vigorously and heated at 100° C. under argon for 12h. After cooling to room temperature the reaction mixture is partitionedbetween brine and ethyl acetate. The organics are dried over magnesiumsulfate, filtered, concentrated on a rotary evaporator, and purified viasilica gel chromatography (2-15% ethyl acetate in hexanes) to afford3-bromo-5-fluoro-2-vinylpyridine (2).

Dimethylamine (40 wt. % in water) (34.1 mL, 108 mmol) is added to astirred solution of 3-bromo-5-fluoro-2-vinylpyridine (2, 2.18 g, 10.8mmol) in acetic acid (14.2 mL, 248 mmol). The resulting mixture issealed, stirred vigorously, and heated at 110° C. for 68 h. Aftercooling to room temperature the reaction mixture is poured onto astirred mixture of sodium hydroxide (9.93 g, 248 mmol) and sodiumbicarbonate (4.53 g, 54.0 mmol) in ice water. The resulting mixture isextracted three times with dichloromethane. The combined organics aredried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and purified via silica gel chromatography (0-20% methanolin dichloromethane). Fractions containing the desired product arecombined and concentrated on a rotary evaporator. The residue isconcentrated down from THF twice and dried under high vacuum to afford2-(3-bromo-5-fluoropyridin-2-yl)-N,N-dimethylethan-1-amine (3).

Example 1A.19

A solution of 2,3-dibromo-5-fluoropyridine (1, 10.0 g, 39.2 mmol),tributyl(1-ethoxyvinyl)stannane (1a, 15.5 mL, 43.1 mmol) and lithiumchloride (4.9 g, 117.6 mmol) in N,N-dimethylformamide (100 mL) isdegassed under nitrogen for 10 minutes. Then,bis(triphenylphosphine)palladium(II) dichloride (1.3 g, 1.9 mmol) isadded and the mixture is heated at 100° C. for 4 h. The reaction mixtureis cooled, diluted with water and extracted with diethyl ether. Thecombined organic layer is washed with water, dried over anhydrous sodiumsulphate, filtered and concentrated. The crude product is purified bycolumn chromatography using silica gel (100-200 mesh) and 0-2% ethylacetate in hexane to afford 3-bromo-2-(1-ethoxyvinyl)-5-fluoropyridine(2).

A solution of 3-bromo-2-(1-ethoxyvinyl)-5-fluoropyridine (2, 5.7 g, 23.1mmol) in dichloromethane (60 mL) is cooled to 0° C., hydrochloric acidin 1,4-dioxane (4 m, 10 mL) is added and the mixture is stirred at roomtemperature for 3 h. The reaction mixture is poured into ice cold water,neutralized with sodium bicarbonate and extracted with dichloromethane.The organic layer is dried over anhydrous sodium sulphate, filtered andconcentrated. The crude product is purified by column chromatographyusing silica gel (100-200 mesh) and 0-5% ethyl acetate in hexane toafford 1-(3-bromo-5-fluoropyridin-2-yl)ethan-1-one (3).

A solution of 1-(3-bromo-5-fluoropyridin-2-yl)ethan-1-one (3, 3.8 g,17.4 mmol) in dichloromethane (40 mL) is cooled to 0° C.,diethylaminosulfur trifluoride (23.3 mL, 174.0 mmol) is added; themixture is stirred at room temperature for 48 h and then heated at 40°C. for 72 h. The reaction mixture is cooled, poured into crushed ice(very slowly, in portions), neutralized with sodium bicarbonate andextracted with dichloromethane. The organic layer is dried overanhydrous sodium sulphate, filtered and concentrated. The crude ispurified by column chromatography using silica gel (100-200 mesh) and0-1% ethyl acetate in hexane to afford3-bromo-2-(1,1-difluoroethyl)-5-fluoropyridine (4).

Example 1A.20

(Trimethylsilyl)diazomethane (2 M in diethyl ether) (19.5 mL, 39.1 mmol)is added slowly to a stirred mixture (not all dissolved) of3,5-difluoroisonicotinic acid (1, 5.18 g, 32.6 mmol) in wet Methanol(200 mL) at 0° C. The resulting cloudy mixture is stirred vigorously at0° C. under air. Bubbling is observed during the addition and continuedfor 45 min. Dichloromethane (100 mL) is added followed by more(trimethylsilyl)diazomethane (2 M in diethyl ether) (19.5 mL, 39.1mmol). The resulting clear solution is stirred vigorously at 0° C. underair for 30 min. More (trimethylsilyl)diazomethane (2 M in diethyl ether)(19.5 mL, 39.1 mmol) is added and then more (trimethylsilyl)diazomethane(2 M in diethyl ether) (19.5 mL, 39.1 mmol) is added again until LCMSindicated complete conversion of the starting material. Volatiles areremoved on a rotary evaporator. The residue is taken up indichloromethane and purified via silica gel chromatography (0-50% ethylacetate in hexanes) (dried under high vacuum for only a few seconds) toafford methyl 3,5-difluoroisonicotinate (2).

A solution of piperidine-4-carboxylic acid (2a 1.20 g, 9.27 mmol),ammonium persulfate (2.33 g, 10.2 mmol), and silver nitrate (590 mg,3.47 mmol) in water (8 mL) is added to a stirred mixture of methyl3,5-difluoroisonicotinate (2, 802 mg, 4.63 mmol) in 3% sulfuric acid inwater (8 mL) at 70° C. The resulting brown mixture is heated at 70° C.with vigorous stirring for 10 min (bubbling is observed) and then cooledto room temperature. The reaction mixture is heated at 70° C. and morepiperidine-4-carboxylic acid (1.20 g, 9.27 mmol), ammonium persulfate(2.33 g, 10.2 mmol), and silver nitrate (590 mg, 3.47 mmol) in water (8mL) is added. The reaction mixture is heated at 70° C. for 10 min andthen cooled to room temperature. Repeat this a total of four times. Thereaction mixture is basified with potassium carbonate. All volatiles areremoved on a rotary evaporator. The residue is slurried with 20%methanol in dichloromethane and filtered through Celite. The filter cakeis washed thoroughly with 20% methanol in dichloromethane. The filtrateis concentrated on a rotary evaporator with silica gel and purified viasilica gel chromatography (0-20% methanol in dichloromethane) to affordmethyl 3,5-difluoro-2-(piperidin-4-yl)isonicotinate (3).

2,2,2-Trifluoroethyl trifluoromethanesulfonate (3a, 1.05 mL, 7.32 mmol)is added to a stirred solution of methyl3,5-difluoro-2-(piperidin-4-yl)isonicotinate (3, 625 mg, 2.44 mmol) andN,N-diisopropylethylamine (3.40 mL, 19.5 mmol) in NMP (10 mL) at roomtemperature under argon. The resulting mixture is stirred at roomtemperature under argon for 3 h. The reaction mixture is diluted withethyl acetate, washed three times with brine, dried over magnesiumsulfate, filtered, concentrated on a rotary evaporator, and purified viasilica gel chromatography (0-50% ethyl acetate in hexanes) to affordmethyl3,5-difluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)isonicotinate(4).

Methyl3,5-difluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)isonicotinate (4,505 mg, 1.49 mmol), trimethyltin hydroxide (1.08 g, 5.97 mmol), and DCE(10 mL) are combined in a 100 mL round bottom flask with a stirbar. Theresulting mixture is stirred vigorously and heated at 80° C. under areflux condenser under argon for 1 h and then at 85° C. for 3 h.Volatiles are removed on a rotary evaporator. The residue is taken up in20% methanol in dichloromethane and purified via silica gelchromatography (0-20% methanol in dichloromethane) to afford3,5-difluoro-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)isonicotinic acid(5).

Example 1A.21

Lithium bis(trimethylsilyl)amide (1M in toluene) (2.23 mL, 2.23 mmol) isadded slowly to a stirred solution of tert-butyl4-cyanopiperidine-1-carboxylate (1, 469 mg, 2.23 mmol) and3-bromo-2,5-difluoropyridine (2, 433 mg, 2.23 mmol) in toluene (5 mL) at−78° C. under argon. The cold bath is removed and the resulting orangesolution is allowed to warm to room temperature with stirring underargon and allowed to stir at room temperature for 2 h. 0.2 M HCl inwater (22.3 mL, 4.46 mmol) is added with vigorous stirring. Theresulting mixture is extracted with ethyl acetate. The organics arewashed with brine, dried over magnesium sulfate, filtered, concentratedon a rotary evaporator, and purified via silica gel chromatography(0-50% ethyl acetate in hexanes) to afford tert-butyl4-(3-bromo-5-fluoropyridin-2-yl)-4-cyanopiperidine-1-carboxylate (3).

n-Butyllithium (2.5 M in hexane) (0.48 mL, 1.20 mmol) is added to astirred solution of diisopropylamine (0.18 mL, 1.30 mmol) in THF (4 mL)at 0° C. under argon. The resulting light yellow solution is stirred for10 min at 0° C. and then added slowly to a stirred solution oftert-butyl4-(3-bromo-5-fluoropyridin-2-yl)-4-cyanopiperidine-1-carboxylate (3, 401mg, 1.04 mmol) in THF (7 mL) at −78° C. under argon. The resultingorange reaction mixture is stirred at −78° C. under argon for 30 min andthen carbon dioxide gas is bubbled in for ˜1 min. (orange color fades)After 10 min 0.1 N sodium hydroxide in water (1 mL) is added to quenchthe reaction mixture. The resulting mixture is partitioned between 0.1 Nsodium hydroxide in water (20 mL) and diethyl ether. The organics areextracted twice more with 0.1 N sodium hydroxide in water (5 mL). Theorganics are discarded. The water layer is acidified with 1 N HCl inwater and then extracted four times with ethyl acetate. The organics arewashed with brine, dried over magnesium sulfate, filtered, concentratedon a rotary evaporator, and dried under high vacuum to afford3-bromo-2-(1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)-5-fluoroisonicotinicacid (4).

HATU (366 mg, 0.964 mmol) is added to a stirred solution of3-bromo-2-(1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl)-5-fluoroisonicotinicacid (4, 393 mg, 0.918 mmol) in DMF (6 mL) at room temperature underargon. After 2 min N,N-diisopropylethylamine (0.19 mL, 1.10 mmol) isadded. The resulting orange mixture is stirred at room temperature underargon for 20 min. A solution of acetamidine hydrochloride (174 mg, 1.84mmol) and N,N-diisopropylethylamine (0.80 mL, 4.59 mmol) in DMF (3 mL)(this is heated with a heat gun and sonicated to get all of theacetamidine dissolved) is added. The resulting orange mixture is stirredvigorously at room temperature under argon for 2 h. The reaction mixtureis diluted with ethyl acetate, washed four times with brine, dried overmagnesium sulfate, filtered, and concentrated on a rotary evaporator.Dry THF (10 mL) is added and volatiles are removed on a rotaryevaporator again. The residue is dried under high vacuum for 10 min. Theresidue is dissolved with stirring in THF (15 mL) and cooled to 0° C.under argon. Sodium hydride (44.1 mg, 1.84 mmol) is added. The cold bathis removed and the resulting cloudy orange mixture is stirred vigorouslyat room temperature under argon for 2.5 h. A solution of ammoniumchloride (147 mg, 2.75 mmol) in water (2 mL) is added and then theresulting mixture is partitioned between ethyl acetate and brine. Theorganics are dried over magnesium sulfate, filtered, concentrated on arotary evaporator, and purified via silica gel chromatography (20-100%ethyl acetate in hexanes) to afford tert-butyl4-(5-bromo-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-cyanopiperidine-1-carboxylate(5).

tert-Butyl4-(5-bromo-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-cyanopiperidine-1-carboxylate(5, 313 mg, 0.698 mmol), ethanol (17 mL), and lithium hydroxide (1 M inwater) (6.98 mL, 6.98 mmol) are combined in a sealable vessel with astirbar. The resulting mixture is sealed, stirred vigorously, and heatedat 120° C. with an oil bath for 44 h. After cooling to room temperaturethe reaction mixture is diluted with methanol and concentrated on arotary evaporator. The residue is taken up in NMP, methanol, and aceticacid (0.60 mL, 10.5 mmol), filtered, and purified via preparatory HPLC(15-60% acetonitrile in water with 0.1% TFA). Fractions containing thedesired product are combined and lyophilized to dryness to affordtert-butyl4-(5-bromo-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-carbamoylpiperidine-1-carboxylate(6).

A stirred mixture of tert-butyl4-(5-bromo-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)-4-carbamoylpiperidine-1-carboxylateTFA salt (6, 186 mg, 0.321 mmol) in 6 M HCl in water (7 mL) is heated at140° C. with an oil bath for 2 min and then sealed, stirred vigorously,and heated at 140° C. with an oil bath for 2 h. More 6 M HCl in water (3mL) is added and heating at 140° C. with an oil bath continued foranother 21 h. After cooling to room temperature the reaction mixture isdiluted with methanol, filtered, and purified via preparatory HPLC(5-18% acetonitrile in water with 0.1% TFA). Fractions containing thedesired product are loaded onto a Strata X-C ion exchange column fromPhenomenex. The column is washed sequentially with water, acetonitrile,methanol, and then 5% ammonium hydroxide in methanol. Eluent containingthe desired product is concentrated on a rotary evaporator and driedunder high vacuum to afford5-bromo-2-methyl-6-(piperidin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (7).

Example 1A.22

To a solution of 5-fluoropyridin-2-ol (1, 9.00 g, 0.079 mol) intetrahydrofuran (290 mL) at 0° C., Trimethylphenylammonium tribromide(29.9 g, 0.079 mol) is added slowly and reaction mixture is stirred atroom temperature for 16 h. After 16 h, the reaction mixture ispartitioned between ethyl acetate and water. Aqueous layer is separatedand re-extracted with ethyl acetate. The combined organic layer iswashed with 5% sodium metabisulphite solution, saturated brine solution,dried over anhydrous sodium sulphate, filtered and concentrated to getcrude product. The crude product is purified by column chromatographyusing silica gel (100-200 mesh) and 0-30% ethyl acetate in hexanesafford 3-bromo-5-fluoropyridin-2-ol (2) as off white solid. Yield: 4.90g, 27%; MS (ESI) m/z 189.99 [M−1]−.

To a solution of 3-bromo-5-fluoropyridin-2-ol (2, 4.10 g, 0.021 mol) inN,N-dimethylformamide (40 mL), cesium carbonate (3.48 g, 0.031 mol) andsodium 2-bromo-2,2-difluoroacetate (2a, 5.05 g, 0.025 mmol) are addedand the reaction mixture is heated at 70° C. for 4 h. After completion,reaction mixture cooled down and partitioned between diethyl ether andwater. Aqueous layer is separated and re-extracted with diethyl ether.The combined organic layer is washed with water, saturated brinesolution, dried over anhydrous sodium sulphate, filtered andconcentrated to get crude product. The crude product is purified bycolumn chromatography using silica gel (100-200 mesh) and hexane aseluent to afford 3-bromo-2-(difluoromethoxy)-5-fluoropyridine (3)

Example 1B. Methods of Synthesizing the Right-Hand Side Example 1B.1

A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (B, 1.1 equiv.) and1,1,1-triethoxyethane (C, 0.7 M) is stirred and heated at 90° C. for 2h. methyl 4-aminothiophene-3-carboxylate (A, 1 equiv.) is addedportionwise at 90° C. under argon atmosphere and heating at 90° C.continued for 6 h. The reaction mixture is cooled to room temperature,water added, and the mixture extracted with ethyl acetate. The organiclayer is dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The crude product is triturated with diethyl ether to affordmethyl4-((1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethyl)amino)thiophene-3-carboxylate(D).

A solution of methyl4-((1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethyl)amino)thiophene-3-carboxylate(D, 1 equiv.) in Dowtherm A (0.5 M), is heated at 235° C. for 4 h. Aftercompletion, the reaction mass is cooled to room temperature, theprecipitated solid isolated by filtration and dried in vacuo. The solidobtained is washed with diethyl ether to afford methyl7-hydroxy-5-methylthieno[3,2-b]pyridine-3-carboxylate (E).

To a solution of methyl7-hydroxy-5-methylthieno[3,2-b]pyridine-3-carboxylate (E, 1 equiv.) in1,2-dichloroethane (0.22 M) are added phosphoryl trichloride (3 equiv.)and a catalytic amount of N,N-dimethylformamide at room temperature andthe reaction mixture heated at 90° C. for 6 h. The reaction mixture isconcentrated under reduced pressure, diluted with ice cold water, andthe solution basified with 10% aqueous sodium hydroxide solution to pH˜7-8 followed by extracted with ethyl acetate. The organic layer isdried over anhydrous sodium sulfate, filtered, concentrated, andpurified by column chromatography to afford methyl7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate (F1).

To a solution of methyl7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate (F1, 1 equiv.) inmixture of methanol (1.7 M), water (1.7 M) and tetrahydrofuran (0.64 M)is added lithium hydroxide monohydrate (2 equiv.) at room temperatureand the resulting mixture is stirred for 2 h. The solid is filtered, thefiltrate is concentrated and combined with the solid. The combinedsolids are acidified with saturated citric acid solution (up to pH=1)and filtered. The resulting solid is washed with methanol followed bydiethyl ether and dried under high vacuum to afford7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (F2).

To a solution of 7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylicacid (F2, 1 equiv.) in tert-butyl alcohol (0.4 M) is added4-dimethylaminopyridine (1 equiv.) and Boc-anhydride (3 equiv.) at roomtemperature. The mixture is stirred for 48 h at 90° C. and the reactionmixture is concentrated under reduced pressure. The crude product ispurified by column chromatography over silica gel to afford tert-butyl7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate (F3).

To a solution of tert-butyl7-chloro-5-methylthieno[3,2-b]pyridine-3-carboxylate (F3, 1 equiv.) and(5-chloro-2-hydroxyphenyl)boronic acid (G, 1.2 equiv.), in 1,4-dioxane(0.5 M) and water (1.2 M) is added potassium carbonate solution (2equiv.) at room temperature and the reaction mixture degassed with argonfor 20 minutes. [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (0.05 equiv.) is added and mixture heated at 90° C. for 2 h.The reaction mixture is cooled to room temperature and filtered and thesolid, washed with water followed by methanol, and dried under vacuum toafford tert-butyl7-(5-chloro-2-hydroxyphenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(H).

To a solution of tert-butyl7-(5-chloro-2-hydroxyphenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(H, 1 equiv.) in acetone (0.28 M) are added potassium carbonate (3.5equiv.) and 1,2-dibromoethane (I, 5.0 equiv.) at room temperature andthe reaction mixture heated at 40° C. for 12 h. An additional 5.0 equiv.of 1,2-dibromoethane is then added at room temperature and the mixtureheated to 45° C. The reaction mixture is filtered through a sinteredfunnel, washed with acetone, and the filtrate concentrated and purifiedby column chromatography to afford tert-butyl7-(2-(2-bromoethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(J).

Example 1B.2

A solution of 2-bromo-4-chloro-1-iodobenzene (A, 1 equiv.) andprop-2-yn-1-ol (B, 1.3 equiv.) in triethylamine (0.3 M) is degassed withargon for 10 min. Copper(I) iodide (0.15 equiv.) andbis(triphenylphosphine)palladium chloride (0.08 equiv.) are added andthe reaction mixture stirred at room temperature for 16 h. The reactionmass is concentrated under reduced pressure and the crude compoundpurified by Combi-flash to afford3-(2-bromo-4-chlorophenyl)prop-2-yn-1-ol (C).

To a solution of 3-(2-bromo-4-chlorophenyl)prop-2-yn-1-ol (C, 1 equiv.)in tetrahydrofuran (0.8 M) are added imidazole (3 equiv.),4-dimethylaminopyridine (0.045 equiv.) andtert-butyldimethylchlorosilane (1.2 equiv.) at room temperature and thereaction mixture stirred for 24 h. The reaction mass is diluted withwater, extracted with ethyl acetate and the organic layer separated,dried over anhydrous sodium sulphate, and purified by Combi-flash toafford((3-(2-bromo-4-chlorophenyl)prop-2-yn-1-yl)oxy)(tert-butyl)dimethylsilane(D).

To a solution of((3-(2-bromo-4-chlorophenyl)prop-2-yn-1-yl)oxy)(tert-butyl)dimethylsilane(D, 1 equiv.) in tetrahydrofuran (0.14 M) is added dropwisen-butyllithium (1.23 M in hexanes, 1.3 equiv.) at −78° C. and themixture stirred at −78° C. for 1 h.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (E, 1.2 equiv.) isadded dropwise at −78° C. and stirring continued for 1 h. The reactionis quenched with chilled water, extracted with ethyl acetate, and theorganic layer separated, dried over anhydrous sodium sulphate,concentrated, and purified by Combi-flash to affordtert-butyl((3-(4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)prop-2-yn-1-yl)oxy)dimethylsilane(F).

Example 1B.3

To a solution of methyl7-(2-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.) in tetrahydrofuran (0.21 M) is added tetra-n-butylammoniumfluoride (1.2 equiv.) at room temperature and the mixture stirred for 2h. The reaction mass is diluted with ethyl acetate, washed with coldwater and the organic layer separated, dried over anhydrous sodiumsulphate, concentrated, and triturated with diethyl ether to affordmethyl7-(5-chloro-2-(3-hydroxyprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(B).

To a solution of methyl7-(5-chloro-2-(3-hydroxyprop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(B, 1 equiv.) in dichloromethane (10.0 mL) is added triphenylphosphine(1.5 equiv.) at room temperature and the reaction mixture cooled to 0°C. Carbontetrabromide (1.5 equiv.) is added and the reaction mixturestirred for 3 h at room temperature. The reaction mass is concentratedand purified by Combi-flash to afford methyl7-(2-(3-bromoprop-1-yn-1-yl)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(C).

Example 1B.4

A solution of methyl7-hydroxy-5-methylthieno[3,2-b]pyridine-3-carboxylate (A, 1 equiv.) andphosphorous oxybromide (10 equiv.) in 1,2 dichloroethane (0.45 M) isheated at 80° C. for 16 h. The reaction mixture is cooled to roomtemperature, quenched with aqueous solution of sodium bicarbonate,extracted with dichloromethane, and the combined organic layer washedwith brine, dried over anhydrous sodium sulphate, filtered,concentrated, and purified by column chromatography to afford methyl7-bromo-5-methylthieno[3,2-b]pyridine-3-carboxylate (B).

A solution of methyl 7-bromo-5-methylthieno[3,2-b]pyridine-3-carboxylate(B, 1 equiv.) and lithium hydroxide (3 equiv.) inmethanol:tetrahydrofuran:water solvent mixture (1:2:1, 0.25 M) isstirred at room temperature for 16 h. The reaction is diluted withwater, cooled to 0° C. and acidified with 1 N hydrochloric acid to pH˜5. The precipitate is filtered, washed with pentane and dried to afford7-bromo-5-methylthieno[3,2-b]pyridine-3-carboxylic acid (C)

To a solution of 7-bromo-5-methylthieno[3,2-b]pyridine-3-carboxylic acid(C, 1 equiv.) and methanesulfonamide (D, 1.5 equiv.) in dichloromethane(0.16 M), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride(2 equiv.) and N,N-dimethylpyridin-4-amine (2.5 equiv.) are added atroom temperature and the mixture stirred for 16 h. The reaction isdiluted with water, cooled to 0° C., acidified with 1 N hydrochloricacid to pH ˜2 and extracted with dichloromethane. The combined organiclayer is dried over anhydrous sodium sulphate, concentrated, andpurified by column chromatography to afford7-bromo-5-methyl-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide(E).

Example 1B.5

To a solution of tert-butyl7-bromo-5-methylthieno[3,2-b]pyridine-3-carboxylate (1, 1.50 g, 4.5mmol) in 1,4-dioxane is added selenium dioxide (0.55 g, 5.02 mmol) andreaction mixture is heated at 95° C. for 8 h. After completion, thereaction mixture is filtered over Celite bed and washed with ethylacetate. The filtrate obtained is concentrated under reduced pressure toget crude product. The crude product obtained is purified by columnchromatography using silica gel (100-200 mesh) and 10% ethyl acetate inhexanes to afford tert-butyl7-bromo-5-formylthieno[3,2-b]pyridine-3-carboxylate (2).

To a solution of tert-butyl7-bromo-5-formylthieno[3,2-b]pyridine-3-carboxylate (2, 0.55 g, 1.62mmol) in methanol (6 mL) at 0° C. is added sodium borohydride (0.12 g,3.25 mmol) and reaction mixture is stirred at same temperature for 1hour. After completion, the reaction mixture is quenched with ice waterand concentrated under reduced pressure. The crude material is dissolvedin ethyl acetate, washed with water, brine solution, dried overanhydrous sodium sulphate, filtered and concentrated to get crudecompound. The crude compound obtained is purified by columnchromatography using silica gel (100-200 mesh) and 20% ethyl acetate inhexanes to afford tert-butyl7-bromo-5-(hydroxymethyl)thieno[3,2-b]pyridine-3-carboxylate (3).

To a solution of tert-butyl7-bromo-5-(hydroxymethyl)thieno[3,2-b]pyridine-3-carboxylate (3, 0.325g, 0.94 mmol) in dichloromethane (5 mL) at −78° C., DAST (0.18 mL, 1.41mmol) is added and reaction mixture is stirred at −78° C. for 1 hour.After completion, reaction mixture is quenched with ice cold water andextracted with dichloromethane. The organic layer is washed saturatedsolution of sodium bicarbonate, dried over anhydrous sodium sulphate,filtered and concentrated to get crude compound. The crude compoundobtained is purified by column chromatography using silica gel (100-200mesh) and 10% ethyl acetate in hexane to get tert-butyl7-bromo-5-(fluoromethyl)thieno[3,2-b]pyridine-3-carboxylate (4).

Example 1B.6

A solution of tert-butyl7-bromo-5-methylthieno[3,2-b]pyridine-3-carboxylate (1, 500.0 mg, 1.523mmol), Azobisisobutyronitrile (24.98 mg, 0.152 mmol) andN-Bromosuccinimide (271.13 mg, 1.523 mmol) in carbon tetrachloride (10mL) is stirred at 90° C. for 5 h. After completion, reaction mixture isconcentrated under reduced pressure and is diluted with dichloromethaneand silica gel is added. The solvent is evaporated. The crude silicamixture is purified by Isco column chromatography using 0-10% methanolin dichloromethane as eluent. The desired fractions are concentratedunder reduced pressure to afford tert-butyl7-bromo-5-(bromomethyl)thieno[3,2-b]pyridine-3-carboxylate (2)

To a stirred solution of tert-butyl7-bromo-5-(bromomethyl)thieno[3,2-b]pyridine-3-carboxylate (2, 0.200 g,0.491 mmol) in methanol (0.2 mL) and N-methylpyrrolidone (2.0 mL) isadded cesium carbonate (0.480 g, 1.474 mmol) at RT and reaction mixtureis stirred at room temperature for 8 h. After completion, the reactionmixture is diluted with dichloromethane and then silica gel is added.The solvent is then evaporated and the free flow silica gel is thenloaded on the column and purified via silica gel chromatography elutingwith methanol in dichloromethane to afford tert-butyl7-bromo-5-(methoxymethyl)thieno[3,2-b]pyridine-3-carboxylate (3).

Example 1B.7

To a stirred solution of 4-methoxybenzyl alcohol (8.1 g, 59.1 mmol) inN,N-dimethylformamide (100 mL) at 0° C., sodium hydride (3.1 g, 65.0mmol) is added. This reaction mixture is stirred at 0° C. for 30 min.Then, 7-chlorothieno[3,2-b]pyridine (1, 10 g, 59.1 mmol) is added at 0°C. and reaction mixture is stirred for 16 h at room temperature. Afterthis time, the mixture is poured into ice. The resulting precipitate iscollected by filtration and dried under reduced pressure to afford7-((4-methoxybenzyl)oxy)thieno[3,2-b]pyridine (2).

To a stirred solution of 7-((4-methoxybenzyl)oxy)thieno[3,2-b]pyridine(2, 8.0 g, 29.5 mmol) in dry tetrahydrofuran (250 mL), n-butyllithium(2.3 M in hexanes, 38.0 mL, 64.9 mmol) is added dropwise at −78° C. Thisreaction mixture is stirred at the same temperature for 45 min. Then,carbon tetrabromide (9.7 g, 29.5 mmol) is added at −78° C. and themixture is stirred at same temperature for 1 h. After this time, thereaction is quenched with saturated aqueous ammonium chloride solutionand extracted with ethyl acetate. The organic layer is washed withwater, dried over anhydrous sodium sulfate, filtered, and concentrated.The crude product is purified by silica gel (100-200 mesh) columnchromatography using 15% ethyl acetate in hexanes as eluent. The desiredfractions are concentrated under reduced pressure to afford2-bromo-7-((4-methoxybenzyl)oxy)thieno[3,2-b]pyridine (3).

A solution of 2-bromo-7-((4-methoxybenzyl)oxy)thieno[3,2-b]pyridine (3,6.5 g, 18.62 mmol) in a mixture of trifluoroacetic acid anddichloromethane (1:1, 40 mL) is stirred at room temperature for 8 h.After this time, the reaction mixture is concentrated under reducedpressure. The crude product is recrystallized with ether and pentanes toafford 2-bromothieno[3,2-b]pyridin-7-ol (4).

To a solution of 2-bromothieno[3,2-b]pyridin-7-ol (4, 3.5 g, 15.28 mmol)in methanol (30 mL), 30% sodium methoxide in methanol (14.0 g, inmethanol, 76.4 mmol) and copper(I) bromide (0.200 g, 1.5 mmol) areadded. This reaction mixture is stirred at 120° C. for 30 h. After thistime, the reaction mixture is concentrated under reduced pressure,acidified with 2 N hydrochloric acid to pH˜6, and extracted with 10%methanol in dichloromethane. The organic layer is dried over anhydroussodium sulfate, filtered, and concentrated to afford2-methoxythieno[3,2-b]pyridin-7-ol (5).

A mixture of 2-methoxythieno[3,2-b]pyridin-7-ol (5, 1.7 g, 9.39 mmol)and phosphoryl chloride (10 mL) is heated and stirred at 90° C. for 6 h.After this time, the reaction mixture is quenched with ice, treated withaqueous 50% sodium hydroxide solution, and extracted with ethyl acetate.The organic layer is washed with water and then saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The crude product is purified by Combiflash using 30% ethyl acetate inhexanes as eluent. The desired fractions are concentrated under reducedpressure to afford 7-chloro-2-methoxythieno[3,2-b]pyridine (6).

To a solution of 3-bromo-7-chloro-2-methoxythieno[3,2-b]pyridine (6, 0.8g, 4.02 mmol) in N,N-dimethylformamide (10 mL) at room temperature,N-bromosuccinimide (1.4 g, 8.04 mmol) is added. This reaction mixture isstirred for 30 min. Then, the reaction mixture is poured into ice andextracted with ethyl acetate. The organic layer is washed with brine,dried over anhydrous sodium sulfate, filtered, and concentrated todryness under reduced pressure. The crude product is purified byCombiflash (12 g, RediSep column) using 10% ethyl acetate in hexanes aseluent. The desired fractions are concentrated under reduced pressure toafford 3-bromo-7-chloro-2-methoxythieno[3,2-b]pyridine (7).

To a stirred solution of 3-bromo-7-chloro-2-methoxythieno[3,2-b]pyridine(7, 0.7 g, 2.52 mmol) in dry tetrahydrofuran (10 mL), n-butyllithium(2.3 M in hexanes, 1.97 mL, 4.54 mmol) is added dropwise at −78° C. Thisreaction mixture is stirred at the same temperature for 45 min. Drycarbon dioxide gas is bubbled through the reaction mixture, which isslowly warmed up to room temperature and stirred for 16 h. The reactionmixture is quenched with 10% aqueous citric acid solution and extractedwith 10% methanol in dichloromethane. The organic layer is dried overanhydrous sodium sulfate, filtered, and concentrated to afford7-chloro-2-methoxythieno[3,2-b]pyridine-3-carboxylic acid (8).

To a solution of 7-chloro-2-methoxythieno[3,2-b]pyridine-3-carboxylicacid (8, 0.5 g, 2.05 mmol) in N,N-dimethylformamide (5.0 mL) at roomtemperature, potassium carbonate (0.85 g, 6.17 mmol) and methyl iodide(0.32 g, 2.26 mmol) are added. This reaction mixture is stirred for 16h. After this time, the reaction mixture is poured into ice andextracted with ethyl acetate. The organic layer is washed with brine,dried over anhydrous sodium sulfate, filtered, and concentrated todryness under reduced pressure. The crude product is purified byCombiflash (12 g, RediSep column) using 2% methanol in dichloromethaneas eluent. The desired fractions are concentrated under reduced pressureto afford methyl 7-chloro-2-methoxythieno[3,2-b]pyridine-3-carboxylate(9).

Example 1B.8

To a stirred solution of 3-bromobenzoic acid (1, 100.0 g, 497.5 mmol) inN,N-dimethylformamide (800 mL), carbodiimidazole (112.9 gm, 696.5 mmol)is added at room temperature and the reaction mixture is heated andstirred at 50° C. for 1 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene (105.8 gm,696.5 mmol) and tert-butanol (184.37 gm, 2487.5 mmol) are added at 50°C. and the reaction mixture is continued to stir at 50° C. for 16 h.After completion, the reaction mass is quenched with water and extractedwith ethyl acetate. The organic layer is separated, dried over anhydroussodium sulphate and concentrated under reduced pressure. The crudeproduct obtained is purified by column chromatography using 100-200silica gel and 2% ethyl acetate in hexanes as eluent. The desiredfractions are concentrated under reduced pressure to afford tert-butyl3-bromobenzoate (2).

A stirred solution of tert-butyl 3-bromobenzoate (2, 113.0 g, 439.4mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3,167.43 gm, 659.1 mmol) and potassium acetate (107.65 gm, 1098.5 mmol) indioxane (600 mL) is degassed with argon for 30 min. Then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) is added andthe reaction mixture is heated and stirred at 85° C. for 16 h. Aftercompletion, the reaction mass is quenched with water and extracted withethyl acetate. The organic layer is separated, dried over anhydroussodium sulphate and concentrated under reduced pressure to obtain thecrude mass. This crude compound is purified by column chromatographyusing 100-200 silica gel and 3% ethyl acetate in hexanes as eluent. Thedesired fractions are concentrated under reduced pressure to affordtert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4).

A stirred solution of 4-chloro-2-iodophenol (5, 60.0 g, 235.8 mmol),tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4,100.37 g, 330.1 mmol) and potassium carbonate (97.76 g, 707.4 mmol) in amixture of dioxane and water (4:1, 1.0 Lit) is degassed with argon for30 min. Palladium(II)bis(triphenylphosphine) dichloride is added at roomtemperature and stirred the reaction mixture at 100° C. for 6 h. Aftercompletion, the reaction mass is quenched with water and extracted withethyl acetate. The organic layer is separated, dried over anhydroussodium sulphate and concentrated under reduced pressure. The crudecompound obtained is purified by column chromatography using 100-200silica gel and 4% ethyl acetate in hexanes as eluent. The desiredfractions are concentrated under reduced pressure to afford tert-butyl5′-chloro-2′-hydroxy-[1,1′-biphenyl]-3-carboxylate (6).

To a stirred solution of tert-butyl5′-chloro-2′-hydroxy-[1,1′-biphenyl]-3-carboxylate (6, 55.0 g, 180.5mmol) in 1 N aqueous solution of sodium hydroxide (1.1 Lit),tetrabutylammoniumbromide (8.72 g, 27.07 mmol) and potassium iodide(4.49 g, 27.07 mmol) are added at room temperature and the reaction massis heated to 90° C. 1,2-Dibromoethane (7, 57.82 mL, 667.89 mmol) isadded slowly at 90° C. and the reaction mixture is stirred at 90° C. for16 h. After completion, the reaction mass is extracted withdichloromethane. The organic layer is dried over sodium sulfate,filtered and concentrated under reduced pressure to obtain the crudemass. The crude compound is purified by column chromatography using100-200 silica gel and 2% ethyl acetate in hexanes to afford tert-butyl2′-(2-bromoethoxy)-5′-chloro-[1,1′-biphenyl]-3-carboxylate (8).

Example 1B.9

To a stirred solution of ethyl 2-(diethoxyphosphoryl)acetate (2, 23.01g, 102.7 mmol) in tetrahydrofuran (100 mL) at 0° C., sodium hydride(60%) (5.47 g, 136.9 mmol) is added and the reaction mixture is stirredat 0° C. for 1 h. 2-bromo-4-chlorobenzaldehyde (1, 15.0 g, 68.4 mmol) intetrahydrofuran (3 mL) is added slowly and the reaction mixture isstirred at 0° C. for 2 h. After completion, the reaction mass isquenched with water and extracted with ethyl acetate. The organic layeris separated, dried over anhydrous sodium sulphate and concentratedunder reduced pressure to get the crude mass. The crude material ispurified by Combi-flash using 3% ethyl acetate in hexanes as eluent. Thedesired fractions are concentrated under reduced pressure to affordethyl (E)-3-(2-bromo-4-chlorophenyl)acrylate (3).

To a stirred solution of ethyl (E)-3-(2-bromo-4-chlorophenyl)acrylate(3, 2.0 g, 17.3 mmol) in dichloromethane (15.0 mL), diisobutylaluminiumhydride (1 M in toluene) (31.1 mL, 31.1 mmol) is added and stirred at−78° C. for 1 h. The reaction mixture is slowly allowed to roomtemperature and stirred for 1 h. After completion, the reaction mass isquenched with aqueous ammonium chloride solution and extracted withdichloromethane. The organic layer is separated, dried over anhydroussodium sulphate and concentrated under reduced pressure to get the crudemass which is purified by Combi-flash using 13% ethyl acetate in hexanesas eluent. The desired fractions are concentrated under reduced pressureto afford (E)-3-(2-bromo-4-chlorophenyl)prop-2-en-1-ol (4).

A stirred solution of (E)-3-(2-bromo-4-chlorophenyl)prop-2-en-1-ol (4,1.5 g, 6.07 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5, 2.03 g, 6.68mmol), and potassium carbonate (2.51 g, 18.2 mmol) in a mixture ofdioxane and water (4:1) (24.0 mL) is degassed with argon for 30 min.[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.222 g,0.3 mmol) is added and the reaction mixture is heated at 90° C. for 12h. After completion, the reaction mass is quenched with water andextracted with ethyl acetate. The organic layer is separated, dried overanhydrous sodium sulphate and concentrated under reduced pressure to getthe crude mass. The crude compound is purified by Combi-flash using 15%ethyl acetate in hexanes as eluent. The desired fractions areconcentrated under reduced pressure to afford tert-butyl(E)-5′-chloro-2′-(3-hydroxyprop-1-en-1-yl)-[1,1′-biphenyl]-3-carboxylate(6).

To a stirred solution of tert-butyl(E)-5′-chloro-2′-(3-hydroxyprop-1-en-1-yl)-[1,1′-biphenyl]-3-carboxylate(6, 1.5 g, 4.34 mmol) and triethylamine (1.82 mL, 13.04 mmol) indichloromethane at 0° C., methanesulfonyl chloride (0.67 mL, 8.69 mmol)is added and the reaction mixture is slowly allowed to room temperatureand stirred for 16 h. After completion, the reaction mass is quenchedwith water and extracted with dichloromethane. The organic layer isseparated, dried over anhydrous sodium sulphate and concentrated underreduced pressure to get the crude material. The crude compound ispurified by Combi-flash using 10% ethyl acetate in hexanes as eluent toafford tert-butyl(E)-5′-chloro-2′-(3-chloroprop-1-en-1-yl)-[1,1′-biphenyl]-3-carboxylate(7).

Example 1B.10

A stirred solution of 2-bromo-4-chloro-1-iodobenzene (1, 1.0 g, 3.15mmol), prop-2-yn-1-ol (2, 0.2 mL, 3.47 mmol) & copper(I) iodide (0.024g, 0.126 mmol) in triethyl amine (30 mL) is degassed with argon for 20min. Dichlorobis(triphenylphosphine)palladium(II) (0.110 g, 0.15 mmol)is added and the reaction mixture is stirred at room temperature for 16h. After completion, the reaction mass is quenched with water andextracted with ethyl acetate. The organic layer is separated, dried overanhydrous sodium sulphate and concentrated under reduced pressure toobtain the crude material. This crude compound is purified byCombi-flash using 10% ethyl acetate in hexanes as eluent. The desiredfractions are concentrated under reduced pressure to afford3-(2-bromo-4-chlorophenyl)prop-2-yn-1-ol (3) as yellow solid. Yield:0.725 g, 93%, MS no ionization.

To a stirred solution of 3-(2-bromo-4-chlorophenyl)prop-2-yn-1-ol (3,0.72 g, 2.93 mmol) in dichloromethane (10 mL), thionyl chloride (0.85mL, 11.75 mmol) is added at 0° C. and the reaction mixture is heated andstirred at 50° C. for 16 h. After completion, the reaction massconcentrated under reduced pressure to obtain the crude which ispurified by Combi-flash using 3% ethyl acetate in hexanes as eluent. Thedesired fractions are concentrated under reduced pressure to afford2-bromo-4-chloro-1-(3-chloroprop-1-yn-1-yl) benzene (4)

Example 1C. General Coupling Methods Example 1C1

To a solution of6-chloro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(A, 1 equiv.) in N,N-dimethylformamide (0.2 M solution) is addedpotassium carbonate (3 equiv.) and tert-butyl7-(2-(2-bromoethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(B, 1 equiv.) and the reaction mixture is heated at 60° C. for 16 h. Thereaction mixture is then cooled, diluted with water, and extracted 2×with ethyl acetate. The combined organic layer is washed with water,dried over anhydrous sodium sulfate, filtered, and concentrated invacuo. Purification by silica gel column chromatography affordstert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(C).

Example 1C2

To a solution of6-chloro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(A, 1 equiv.) in N,N-dimethylformamide (0.14 M) is added tert-butyl7-(2-(2-bromoethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(B, 1.3 equiv.), potassium iodide (0.2 equiv.), and ground potassiumcarbonate (3 equiv.) at room temperature. The mixture is stirred for 16h at 50° C., diluted with water, and extracted 2× with ethyl acetatewith ethyl acetate. The combined organic layer is washed with water,dried over anhydrous magnesium sulfate, and concentrated in vacuo.Purification by silica gel column chromatography gives tert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(C).

Example 1C.3. Alternative Coupling Method

To a solution of 3-bromo-5-fluoroisonicotinic acid (A, 5.0 g, 21.92mmol) in dimethylformamide (15 mL), potassium carbonate (6.07 g, 43.84mmol) and iodomethane (2.05 mL, 32.88 mmol) are added at roomtemperature and stirred the reaction mixture for 2 h at roomtemperature. After completion, the reaction mass is diluted with ethylacetate and washed with cold water. The organic layer is separated,dried over anhydrous sodium sulphate, filtered and concentrated to givecrude. The crude is purified by flash chromatography eluting thecompound with ethyl acetate in hexanes (1-10%). The desired fractionsare concentrated under reduced pressure to afford methyl3-bromo-5-fluoroisonicotinate (B).

To a solution of methyl 3-bromo-5-fluoroisonicotinate (B, 4.0 g, 17.17mmol) in dimethylformamide (15 mL), potassium carbonate (7.0 g, 51.51mmol) is added followed by drop wise addition of 4-methoxy benzyl amine(3.52 mL, 25.0 mmol at room temperature The reaction mixture is stirredfor 16 h at 50° C. After completion, the reaction mass is diluted withethyl acetate and washed with cold water. The organic layer is separatedand dried over anhydrous sodium sulphate, filtered and concentrated togive crude. The crude is purified by flash column chromatography elutingthe compound with ethyl acetate in hexanes (10-20%). The desiredfractions are concentrated under reduced pressure to afford methyl3-bromo-5-((4-methoxybenzyl)amino)isonicotinate (C).

To a solution of methyl 3-bromo-5-((4-methoxybenzyl)amino)isonicotinate(C, 2.8 g, 8.0 mmol) in methanol (5.0 mL) and water (5.0 mL) is addedsodium hydroxide (0.64 g, 26.0 mmol) and stirred the reaction mixturefor 6 h at room temperature. After completion, the reaction mass isconcentrated to evaporate methanol. The aqueous layer is cooled to 0° C.and acidified with 2 N hydrochloric acid (pH˜4). The precipitated solidis filtered and dried to afford3-bromo-5-((4-methoxybenzyl)amino)isonicotinic acid (D).

To a solution of 3-bromo-5-((4-methoxybenzyl)amino)isonicotinic acid (D,0.9 g, 26.0 mmol) in dimethylformamide (15 mL), methyl7-(2-(2-aminoethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(E, 1.16 g, 32.0 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (1.48 g, 39.0 mmol) are added at 0° C.Diisopropylethylamine is added drop wise at 0° C. and stirred thereaction mixture at room temperature for 3 h. After completion, thereaction mass is diluted with ethyl acetate and washed with cold water.The organic layer is separated, dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to give crude. Thecrude is purified by flash column chromatography eluting the compoundwith methanol in dichloromethane (2-5%). The desired fractions areconcentrated under reduced pressure to afford methyl7-(2-(2-(3-bromo-5-((4-methoxybenzyl)amino)isonicotinamido)ethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(F).

To a solution of methyl7-(2-(2-(3-bromo-5-((4-methoxybenzyl)amino)isonicotinamido)ethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(F, 1.8 g, 26.0 mmol) in dichloromethane (10 mL) is addedtriflouroacetic acid (10 mL) at 0° C. and is stirred the reactionmixture at room temperature for 2 h. After completion, the reaction massis concentrated to give crude. The crude is triturated with diethylether to afford methyl7-(2-(2-(3-amino-5-bromoisonicotinamido)ethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(G).

To a solution of methyl7-(2-(2-(3-amino-5-bromoisonicotinamido)ethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(G, 1.2 g, 2.1 mmol) in tetrahydofuran (10 mL), 2,2-difluoroaceticanhydride (H, 0.26 mL, 2.1 mmol) is added at 0° C. and stirred thereaction mixture at room temperature for 1 h. After completion, thereaction mass is concentrated to give crude. The crude is purified bywashing and triturating with diethyl ether to afford methyl7-(2-(2-(3-bromo-5-(2,2-difluoroacetamido)isonicotinamido)ethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(I).

A solution of methyl7-(2-(2-(3-bromo-5-(2,2-difluoroacetamido)isonicotinamido)ethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(I, 1.0 g, 1.56 mmol) in acetic acid (10 mL) is heated and stirred at110° C. for 24 h. After completion, acetic acid is removed under reducedpressure to give crude. The crude is purified by flash columnchromatography eluting the compound with ethyl acetate in hexanes(50-70%). The desired fractions are concentrated under reduced pressureto afford methyl7-(2-(2-(5-bromo-2-(difluoromethyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(J).

Example 1D. Post Coupling Modification Methods Example 1D.1

To a solution of cyclopropanol (B, 2.5 equiv.) in tetrahydrofuran (0.6M), sodium hydride (3 equiv.) is added and the reaction mixture stirredat 0° C. for 10 min. tert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.) is added to the reaction mixture at room temperature andheated at 120° C. for 6 h. The reaction mixture is cooled to roomtemperature, diluted with water, extracted with ethyl acetate, and theethyl acetate layer dried over sodium sulfate, concentrated, andpurified over a plug of silica gel to afford tert-butyl7-(5-chloro-2-(2-(5-cyano-6-cyclopropoxy-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(C1).

To a solution of tert-butyl7-(5-chloro-2-(2-(5-cyano-6-cyclopropoxy-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(C1, 1 equiv.) in dichloromethane (0.1 M), triflouroacetic acid (0.1 M)is added at 0° C. The reaction is slowly brought to room temperature andstirred for 16 h. The reaction is concentrated under reduced pressure,washed with diethyl ether, and purified by preparative HPLC to afford7-(5-chloro-2-(2-(5-cyano-6-cyclopropoxy-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylicacid (C2)

Example 1D.2

To a solution of tert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.), and azetidin-3-ol hydrochloride (B, 2 equiv.) in DMF(0.16 M), potassium carbonate (5 equiv.) is added at room temperaturefollowed by heating at 100° C. with stirring for 16 h. The reactionmixture is diluted with water, extracted with ethyl acetate, and theorganic layers washed with water and brine solution, dried over sodiumsulfate, concentrated, and purified by flash chromatography to affordtert-butyl7-(5-chloro-2-(2-(5-cyano-6-(3-hydroxyazetidin-1-yl)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(C).

Example 1D.3

A solution of tert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.), and cesium hydroxide (3 equiv.) in 1,4-dioxane (0.12 M)is degassed under nitrogen for 5 minutes.Tris(dibenzylideneacetone)dipalladium(0) (0.05 equiv.) and5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole (0.03equiv.) are added and the mixture heated at 90° C. for 16 h. Thereaction mixture is cooled, diluted with water, extracted with ethylacetate, and the combined organic layer, dried over anhydrous sodiumsulphate, filtered and concentrated to afford tert-butyl7-(5-chloro-2-(2-(5-cyano-6-hydroxy-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(B).

Example 1D.4

A solution tert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.) in methanolic ammonia (20%, 0.05 M) is heated in a sealedtube at 120° C. for 16 h. The reaction mixture is concentrated to affordtert-butyl7-(2-(2-(6-amino-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(B).

Example 1D.5

To a solution tert-butyl7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(methylamino)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.) in acetic anhydride (B, 0.06 M), acetic acid (0.24 M) isadded at room temperature and the mixture is heated at 120° C. for 27 h.The reaction mixture is quenched on ice, extracted with ethyl acetate,and the organic layer dried over anhydrous sodium sulfate, filtered,concentrated, and purified by preparative HPLC to afford7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(N-methylacetamido)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylicacid (C).

Example 1D.6

A solution tert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.) in methanolic ammonia (20%, 0.05 M) is heated in a sealedtube at 120° C. for 16 h. The reaction mixture is concentrated to affordtert-butyl7-(2-(2-(6-amino-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(B).

Example 1D.7

To a solution of tert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-ethylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.) in N,N-dimethylformamide (0.05 M), 1-methylpiperazine (B,3 equiv.), potassium fluoride (5 equiv.) and 18 crown-6 (1 equiv.) areadded and the mixture heated at 90° C. for 3 h. The reaction mixture iscooled, diluted with water, extracted with ethyl acetate, and thecombined organic layer dried over anhydrous sodium sulphate, filtered,and concentrated to afford tert-butyl7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-ethylthieno[3,2-b]pyridine-3-carboxylate(C).

Example 1D.8

To a solution7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylicacid (A, 1 equiv.) and tert-butyl azetidin-3-yl(methyl)carbamatehydrochloride (B, 2 equiv.) in 1,4-dioxane (0.088 M) is added caesiumcarbonate (0.172 g, 0.530 mmol) and the reaction mixture heated at 90°C. for 3 h. The reaction mixture is diluted with water, extracted withethyl acetate, and the organic layer dried over anhydrous sodiumsulphate, filtered, concentrated, and purified by column chromatographyto afford7-(2-(2-(6-(3-((tert-butoxycarbonyl)(methyl)amino)azetidin-1-yl)-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylicacid (C1).

To a solution of7-(2-(2-(6-(3-((tert-butoxycarbonyl)(methyl)amino)azetidin-1-yl)-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylicacid (C1, 1 equiv.) in dichloromethane (0.045 M), 2,2,2-trifluoroaceticacid (0.14 M) is added at 0° C. and the reaction mixture stirred for 16h at room temperature. The reaction mixture is concentrated and purifiedby preparative HPLC to afford7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(3-(methylamino)azetidin-1-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylicacid (C2)

Example 1D.9

tert-Butyl7-(2-(2-(6-bromo-5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.), 3-aminopyridine (B, 1.1 equiv.), xantphos (0.2 equiv.),cesium carbonate (3 equiv.), andtris(dibenzylideneacetone)dipalladium(0) (0.2 equiv.) are suspended in1,4-dioxane (0.047 M) in a screw capped vial equipped with a stir bar.The reaction mixture is sparged with argon for 3 min, then sealed andheated at 100° C. in a heating block for 75 min. The reaction mixture iscooled to room temperature and taken up in a 1:1 N,Ndimethylformamide:methanol solution and filtered through a syringefilter. Preparatory HPLC affords tert-butyl7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-6-(pyridin-3-ylamino)-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(C).

Example 1D.10

To a stirred solution of oxetan-3-amine (B, 1 equiv.), sodium carbonate(3.5 equiv.) in methanol (0.68 M) and 1,5-dichloropentan-3-one (A, 1equiv.) are added at room temperature and the reaction mixture is heatedat 75° C. for 3 h. The reaction mixture is cooled to room temperature,diluted with water, extracted with ethyl acetate, and the ethyl acetatelayer is dried over sodium sulfate, concentrated, and purified over aplug of silica gel to afford 1-(oxetan-3-yl)piperidin-4-one (C).

To a solution of 1-(oxetan-3-yl)piperidin-4-one (C, 0.8 g, 5.16 mmol) indichloromethane (0.5 M) are added ethylamine (2 M in tetrahydrofuran,1.3 equiv.) and acetic acid (10 M) at room temperature. The reactionmixture is stirred for 60 min and sodium triacetoxyborohydride (1.3equiv.) is added at 0° C. and stirred for 16 h at room temperature. Thereaction is quenched with 10% aqueous sodium hydroxide solution,extracted with methanol in dichloromethane (5%), and the organic layerwashed with sodium chloride solution, dried over anhydrous sodiumsulfate, filtered and concentrated to affordN-ethyl-1-(oxetan-3-yl)piperidin-4-amine (D).

To a solution of tert-butyl7-(5-chloro-2-(3-(5-cyano-6-fluoro-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(E, 1 equiv.) in acetonitrile (0.1 M), are addedN-ethyl-1-(oxetan-3-yl)piperidin-4-amine (D, 2 equiv.) andN,N-diisopropylethylamine (3 equiv.) at room temperature and thereaction mixture is stirred for 30 h at 100° C. The reaction is cool toroom temperature, quenched with water, extracted with ethyl acetate, andthe organic layer washed with sodium chloride solution, dried overanhydrous sodium sulfate, filtered, concentrated and purified by Combiflash to afford tert-butyl7-(5-chloro-2-(3-(5-cyano-6-(ethyl(1-(oxetan-3-yl)piperidin-4-yl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(F).

Example 1D.11

To a solution of tert-butyl(2-(difluoromethyl)pyridin-4-yl)(methyl)carbamate (A, 1 equiv.) andacetic acid (10 equiv.) in methanol (0.029 M), 5% rhodium on carbon (0.5equiv.) is added at room temperature and the mixture heated at 80° C.under 80 psi for 15 hr. The reaction mixture is filtered andconcentrated to afford tert-butyl(2-(difluoromethyl)piperidin-4-yl)(methyl)carbamate (B).

To a solution of tert-butyl(2-(difluoromethyl)piperidin-4-yl)(methyl)carbamate (B, 1 equiv.) in THF(0.19 M) are added formaldehyde (37% solution in water, 10 equiv.),acetic acid (9 equiv.) and molecular sieves (˜3× by weight). The mixtureis stirred for 30 min at room temperature, sodium triacetoxyboranuide(361 mg, 1.7 mmol) is added and the mixture stirred for 30 min. Thereaction mixture is diluted with methanol and the residue passed througha strata ion exchange column, eluting with water three times, thenacetonitrile three times, then methanol three times. tert-Butyl(2-(difluoromethyl)-1-methylpiperidin-4-yl)(methyl)carbamate (C) iseluted by washing the column with a solution of dichloromethane,methanol, and ammonium hydroxide (50:40:10).

tert-Butyl (2-(difluoromethyl)-1-methylpiperidin-4-yl)(methyl)carbamate(C, 1 equiv.) in trifluoroacetic acid (0.006 M) is stirred at roomtemperature for 30 min and the reaction mixture is concentrated toafford 2-(difluoromethyl)-N,1-dimethylpiperidin-4-amine (D).

A mixture of7-(5-chloro-2-(2-(5-cyano-8-fluoro-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (E, 1 equiv.), 2-(difluoromethyl)-N,1-dimethylpiperidin-4-amine (D,5 equiv.) and NMP (0.037 M) in DIPEA (7 equiv.) is stirred at roomtemperature for 30 min. The reaction mixture is filtered and purified byHPLC to afford7-(5-chloro-2-(2-(5-cyano-8-((2-(difluoromethyl)-1-methylpiperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (F).

Example 1D.12

To a dichloromethane (40 mL) solution of tert-butyl7-(5-chloro-2-(3-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.) is added trifluoroacetic acid (0.25 M) at 0° C. andstirred for 17 h at room temperature. The mixture is concentrated invacuo, aqueous sodium bicarbonate solution added, and washed withdiethyl ether. The water layer is acidified with 3 N hydrogen chloridesolution and stirred for 15 min. Filtration affords7-(5-chloro-2-(3-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (B).

To a7-(5-chloro-2-(3-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (B, 1160 mg, 2.12 mmol) solution in dichloromethane (0.11 M) andmethanol (0.42 M) is added trimethylsilyldiazomethane (4 equiv.) at 0°C. Upon stirring for 10 min at 0° C., the reaction is quenched withacetic acid (3.5 M), concentrated and purified by silica gel columnchromatography to afford methyl7-(5-chloro-2-(3-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(C).

To a methyl7-(5-chloro-2-(3-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(C, 433 mg, 0.770 mmol) in N-methyl-2-pyrrolidone (0.21 M) is added1-(2-(trifluoromethoxy)ethyl)piperazine dihydrochloride (D, 1.5 equiv.)at room temperature and the mixture stirred for 2 h at 50° C. followedby 17 h at room temperature. The mixture is diluted with methanol,filtered, and the filtrate purified by preparative HPLC to give methyl7-(5-chloro-2-(3-(5-cyano-2-methyl-4-oxo-6-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(E).

Example 1D.13

To a solution of tert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.) and potassiumtrifluoro(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)borate (B, 1.4 equiv.)in a mixture of toluene and water (2:1, 0.7 M) is added cesium carbonate(2 equiv.) and the reaction mixture degassed with argon for 15 min.[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.1equiv.) is added and heated at 100° C. for 16 h. The reaction mass isfiltered through Celite, washed with ethyl acetate, and the filtratedried over anhydrous sodium sulfate, concentrated, and purified byCombiflash to afford tert-butyl7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(C).

To a stirred solution of tert-butyl7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(C, 1 equiv.) in a mixture of acetonitrile and water (3:1, 0.018 M),selectfluor-II (2 equiv.) is added at 0° C. and the mixture stirred atroom temperature for 48 h. The reaction mixture is partitioned betweenwater and ethyl acetate and the organic layer dried over sodium sulfateand concentrated to afford tert-butyl7-(5-chloro-2-(2-(5-cyano-6-(2-hydroxyethyl)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(D).

To a solution of tert-butyl7-(5-chloro-2-(2-(5-cyano-6-(2-hydroxyethyl)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(D, 1 equiv.) in dichloromethane (0.4 M), diethylaminosulfur trifluoride(1.5 equiv.) is added at 0° C. and the mixture stirred at roomtemperature for 3 h. The reaction mass is quenched with 10% aqueoussodium hydroxide solution at 0° C., extracted with dichloromethane, andthe organic layer dried over anhydrous sodium sulfate and concentratedto afford tert-butyl7-(5-chloro-2-(2-(5-cyano-6-(2-fluoroethyl)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(E).

Example 1D.14

tert-Butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.), PdCl₂(PPh₃)₂ (0.18 equiv.), and(E)-4,4,5,5-tetramethyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-en-1-yl)-1,3,2-dioxaborolane(B, 1.6 equiv.) are suspended in 1,4-dioxane (0.054 M) in an oven driedmicrowave vial equipped with a stir bar. Aqueous potassium carbonate(2.0 M, 4 equiv.) is added, and the sealed vial is sparged with argonfor 5 min and heated at 100° C. in a microwave reactor for 4 h. Thereaction mixture is diluted with saturated aqueous sodium bicarbonateand ethyl acetate and the aqueous phase extracted with ethyl acetatethree times. The combined organic material is washed with brine, driedover magnesium sulfate, filtered, and purified via silica gelchromatography to afford tert-butyl(E)-7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-6-7G(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-en-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(C).

tert-Butyl(E)-7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-en-1-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(C, 1 equiv.) is suspended in methanol (0.05 M) and tetrahydrofuran(0.05 M) and water (0.05 M) in a screw capped vial equipped with a stirbar and the reaction mixture stirred at room temperature whilep-toluenesulfonic acid (0.35 equiv.) is added in 1 portion. After 30 minthe temperature is raised to 55° C. and stirred an additional 1 h. Water(0.1 M) is added and, after 1 h, the temperature raised to 80° C. andheated at this temperature for 8 h. The reaction mixture is cooled toroom temperature and volatile solvent is then removed in vacuo. Thereaction mixture is diluted with saturated aqueous sodium bicarbonateand ethyl acetate, the layers separated, and the aqueous phase extractedwith ethyl acetate three times. The combined organic material is washedwith brine, dried over magnesium sulfate, and the solids filtered andconcentrated to afford tert-butyl(E)-7-(5-chloro-2-(2-(5-cyano-6-(3-hydroxyprop-1-en-1-yl)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(D).

tert-Butyl(E)-7-(5-chloro-2-(2-(5-cyano-6-(3-hydroxyprop-1-en-1-yl)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(D, 1 equiv.) is dissolved in dichloromethane (0.086 M) in an oven-driedscrew capped vial equipped with a stir bar. The reaction mixture isstirred at 0° C. while N,N-diisopropylethylamine (6 equiv.) is addedslowly. Methanesulfonyl chloride (2.6 equiv.) is then added dropwise atwhich time the ice bath is removed. After 30 min the reaction mixture isdiluted with dichloromethane, washed with saturated aqueous sodiumbicarbonate and brine, dried over magnesium sulfate, filtered and thesolvent removed in vacuo, affording tert-butyl(E)-7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(3-((methylsulfonyl)oxy)prop-1-en-1-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(E).

tert-Butyl(E)-7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(3-((methylsulfonyl)oxy)prop-1-en-1-yl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(E, 54.5 mg, 0.07 mmol) is dissolved in 1,2-dichloroethane (0.05 M) in ascrew capped vial equipped with a stir bar and the reaction mixturestirred at 10° C. while 4,4-difluoropiperidine (F, 3.3 equiv.) is addeddropwise. N,N-Diisopropylethylamine (6.6 equiv.) is added dropwise andafter 5 min the reaction mixture is warmed to room temperature. After 15min the temperature is raised to 45° C. and stirring continued for 3 h.The reaction mixture is cooled to room temperature and the solvent isthen removed in vacuo. The residue is taken up in DMF and filteredthrough a syringe filter. Preparatory HPLC afforded the desired product,which is isolated by passing HPLC fractions through a strata ionexchange column, then washing with a solution of dichloromethane,methanol, and ammonium hydroxide. The solvent is to afford tert-butyl(E)-7-(5-chloro-2-(2-(5-cyano-6-(3-(4,4-difluoropiperidin-1-yl)prop-1-en-1-yl)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(G).

Example 1D.15

To a solution of tert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.), tributyl(methoxymethyl)stannane (B, 1.5 equiv.) in1-methyl-2-pyrrolidinone (0.1 M) is degassed using argon for 10 min andtetrakis(triphenylphosphine)palladium (0) (0.055 g, 0.048 mmol) is addedat room temperature and heated at 130° C. for 10 h. The reaction mixtureis cooled to room temperature, diluted with water and, extracted withethyl acetate, and the ethyl acetate layer dried over sodium sulfate,concentrated, and purified by preparative HPLC to afford tert-butyl7-(5-chloro-2-(2-(5-cyano-6-(methoxymethyl)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(C).

Example 1D.16

To a solution of tert-butyl7-(5-chloro-2-(2-(6-chloro-5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(A, 1 equiv.) and (2-fluorophenyl)boronic acid (B, 1.5 equiv.) in1,4-dioxane is added 2 M aqueous potassium carbonate solution (3 equiv.)and reaction mixture degassed with argon gas for 10 min.[1,1′-Bis(diphenylphosphino)ferrocene] dichlopalladium(II)dichlomethanecomplex (0.05 equiv.) is added and degassed with argon gas for 5 min andthe reaction mixture is heated at 90° C. for 3 h. The reaction mixtureis diluted with water, extracted with ethyl acetate, and the organiclayer dried over anhydrous sodium sulphate, filtered, concentrated, andpurified by column chromatography to afford tert-butyl7-(5-chloro-2-(2-(5-cyano-6-(2-fluorophenyl)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(C).

Example 1D.17

To a solution of7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (A, 1 equiv.) and oxetane-3-sulfonamide (B, 2.5 equiv.) indichloromethane (0.07 M) is added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 equiv.)and 4-(dimethylamino)pyridine (2.5 equiv.) at 0° C. and stirred at roomtemperature for 12 h. The reaction mixture is diluted with water,extracted with dichloromethane, and the organic layer dried overanhydrous sodium sulphate, filtered, concentrated, and purified bypreparative HPLC to afford7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)-N-(oxetan-3-ylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide(C).

Example 1D.18

To a stirred solution of5-bromo-3-(3-(2-bromo-4-chlorophenyl)prop-2-yn-1-yl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(6, 0.6 g, 1.28 mmol) in N,N-dimethylformamide, copper(I) cyanide (0.138g, 1.53 mmol) is added and the reaction mixture is heated and stirred at90° C. for 16 h. After completion, the reaction mass is diluted withethyl acetate and washed with cold water. The organic layer isseparated, dried over anhydrous sodium sulphate and concentrated underreduced pressure. The crude compound is purified by Combi-flash using50% ethyl acetate in hexanes as eluent. The desired fractions areconcentrated under reduced pressure to afford3-(3-(2-bromo-4-chlorophenyl)prop-2-yn-1-yl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(7).

A stirred solution of3-(3-(2-bromo-4-chlorophenyl)prop-2-yn-1-yl)-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(7, 0.1 g, 0.24 mmol), 4-boronophthalic acid (8, 0.075 g, 0.36 mmol) andpotassium carbonate (0.099 g, 0.72 mmol) in a mixture of dioxane,N,N-dimethylformamide and water (1.2 mL, 0.6 mL, 0.2 mL respectively) isdegassed with argon for 25 min.Dichlorobis(triphenylphosphine)palladium(II) is added and the reactionmixture is heated and stirred at 90° C. for 2 h. After completion,volatiles are removed under reduced pressure to obtain the residue. Thisresidue is diluted with water, acidified with 1 N aqueous hydrochloricacid and extracted with ethyl acetate. The organic layer is separated,dried over anhydrous sodium sulphate and concentrated under reducedpressure to obtain the compound. This compound is purified bypreparative HPLC to afford5′-chloro-2′-(3-(5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)-[1,1′-biphenyl]-3,4-dicarboxylicacid (9).

Example 1D.18

To a solution of methyl2-amino-5′-chloro-2′-(2-(5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-[1,1′-biphenyl]-3-carboxylate(3, 1.5 g, 3.06 mmol) in acetonitrile (40 mL), tert-butyl nitrite (0.50g, 4.8 mmol) is added at room temperature. Suspension of copper(I)iodide (0.93 g, 3.06 mmol) in acetonitrile (10 mL) is added drop wiseover a period of 10 min at room temperature. The reaction mixture isstirred at 60° C. for 4 h. After completion, the reaction mixture isdiluted with water and extracted with ethyl acetate. The organic layeris washed with aqueous sodium thiosulphate, dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to affordcrude. The crude is purified by flash column chromatography using 0-40%ethyl acetate in hexane to afford methyl5′-chloro-2′-(2-(5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-2-iodo-[1,1′-biphenyl]-3-carboxylate(4).

A solution of methyl5′-chloro-2′-(2-(5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-2-iodo-[1,1′-biphenyl]-3-carboxylate(4, 0.57 g, 0.95 mmol) in dioxane (20 mL) is degassed for 10 min usingargon. Tributyl(ethynyl)stannane (5, 0.6 g, 1.86 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol) are addedand the reaction mixture is stirred at 90° C. for 16 h. Aftercompletion, reaction mixture is diluted with water and extracted withethyl acetate. The organic layer is dried over anhydrous sodium sulfatefiltered and concentrated to dryness under reduced pressure. The crudeis purified by flash column chromatography using 0-40% ethyl acetate inhexanes to afford methyl5′-chloro-2′-(2-(5-cyano-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-2-ethynyl-[1,1′-biphenyl]-3-carboxylate(6).

Compounds made using one or more of the general methods described aboveare shown in Table 1. Where provided, characterization data is to theright of the compounds.

TABLE 1 7-Aza-Thienylpyridine and Derivative Compounds Com- poundCharacterization 34

MS (ESI) m/z 447.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H),9.23 (s, 1H), 9.07 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 7.84 (d, J =7.68, 1H), 7.61 (d, J = 7.72, 1H), 7.45- 7.39 (m, 2H), 7.33 (d, J = 2.5Hz, 1H), 7.21 (d, J = 8.84Hz, 1H), 4.35 (s, 4H) 35

MS (ESI) m/z 462.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H),9.03 (s, 1H), 8.63 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.59(dd, J = 4.8 Hz, 1H), 7.48 (dd, J = 4.4 Hz, 1H), 7.409 (d, J = 2.8 Hz,1H), 7.249 (d, J = 8.8 Hz, 1H), 4.386 (s, 4H), 2.22 (s, 3H) 36

MS (ESI) m/z 486.38 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H),7.87 (d, J = 7.68 Hz, 1H), 7.83 (s, 1H), 7.49 (d, J = 7.68 Hz, 1H),7.43-7.38 (m, 2H), 7.27 (d, J = 2.6 Hz, 1H), 7.20 (d, J = 8.88 Hz, 1H),4.39-4.35 (dd, J = 12.52 Hz, 4H), 2.29 (s, 3H) 38

MS (ESI) m/z 529.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H),9.13 (s, 1H), 7.87-7.85 (m, 2H), 7.56 (d, J = 7.76 Hz, 1H), 7.42-7.38(m, 2H), 7.29 (d, J = 2.64 Hz, 1H), 7.21 (d, J = 8.92 Hz, 1H), 4.37 (m,4H), 2.24 (s, 3H) 39

MS (ESI) m/z 554.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H),9.19 (s, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 7.61 (dd, J =2.64, 8.88, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.45 (d, J = 2.68 Hz, 1H),7.37 (d, J = 8.96 Hz, 1H), 6.72-6.46 (t, J = 51.6 Hz, 1H), 4.41 (d, J =4.64 Hz, 2H), 4.36 (d, J = 4.52 Hz, 2H) 44

MS (ESI) m/z 457.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H),9.18 (s, 1H), 9.04 (s, 1H), 7.9-7.83 (m, 1H), 7.76 (s, 1H), 7.72 (d, J =8.4 Hz, 1H), 7.52-7.44 (m, 3H), 7.36 (d, J = 2.2 Hz, 1H), 6.42-6.35 ( m,1H), 6.22 (d, J = 16.04 Hz, 1H), 4.82 (d, J = 4.8 Hz, 2H), 2.58 (s, 3H)45

MS (ESI) m/z 510.44 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H),8.98 (s, 1H), 8.96 (d, J = 4.56 Hz, 1H), 8.17 (d, J = 7.52 Hz, 1H), 7.64(s, 1H), 7.56 (dd, J = 8.92 Hz, 1H), 7.44 (d, J = 4.56 Hz, 1H), 7.30 (d,J = 2.56 Hz, 1H), 7.26 (d, J = 8.96 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H),4.33-4.29 (m, 2H), 4.24-4.17 (m, 1H), 4.12-4.06 (m, 1H), 1.84 (s, 3H) 48

MS (ESI) m/z 475.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H),9.18 (s, 1H), 9.05 (s, 1H), 7.36 (dd, J = 8.8 Hz, 1H), 7.28 (t, 2H),7.24-7.18 (m, 5 H), 4.57 (t, 2H), 4.33 (t, 2H), 2.87 (t, 2H) 2.57 (t,2H) 49

MS (ESI) m/z 553.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) d 12.17 (bs,1H), 8.84 (d, J = 4.76 Hz, 1H), 8.41 (s, 1H), 7.72 (dd, J = 10.68 Hz,7.56 Hz, 1H),7.60 (dd, J = 8.08, 2.60 Hz, 1H), 7.48 (d, J = 4.76 Hz,1H), 7.41 (d, J = 2.52 Hz, 1H), 7.36 (d, J = 8.08 Hz, 1H), 4.39 (t, J =4.64 Hz, 2H). 4.23 (t, J = 4.68 Hz, 2H), 1.77 (s, 3H) 50

MS (ESI) m/z 619.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J =4.4 Hz, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.60 (dd, J = 8.8, 2.6 Hz, 1H),7.51 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 4.41 (t, J = 4.7 Hz, 2H), 4.25 (t, J = 4.7 Hz, 2H), 1.69 (s, 3H)140

MS (ESI) m/z 518.50 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.029 (d, J =1.24 Hz, 2H), 8.835 (d, J = 4.76 Hz, 1H), 8.379 (s, 1H), 7.596 (dd, J =2.6, 8.96 Hz, 1H), 7.48 (d, J = 4.72 Hz, 1H), 7.439 (d, J = 2.52 Hz,1H), 7.35 (d, J = 9.0 Hz, 1H), 4.403 (t, J = 4.68 Hz, 2H), 4.255 (t, J =6.04 Hz, 2H), 1.787 (s, 3H) 147

MS (ESI) m/z 505 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H),9.00 (s, 1H), 8.139 (m, J = 8.04 Hz, 2H), 7.44 (m, J = 7.92 Hz, 2H),7.28 (d, J = 2.76 Hz, 1H), 7.19 (d, J = 8.92 Hz, 1H), 4.35 (s, 4H), 2.22(s, 3H) 149

MS (ESI) m/z 497.38 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 9.158 (s, 1H),9.033 (s, 1H), 8.291 (s, 1H), 8.117 (d, J = 8.2 Hz, 1H), 7.63 (d, J =8.28 Hz, 1H), 7.6 (dd, J = 1.96, 8.12 Hz, 1H), 7.53 (d, J = 1.96 Hz,1H), 7.49 (dd, J = 2.2, 8.4 Hz, 1H), 5.05 (s, 2H), 2.35 (s, 3H) 150FA

MS (ESI) m/z 497 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H),9.03 (s, 1H), 7.68- 7.63 (m, 2H), 7.47-7.38 (m, 3H), 7.23 (d, J = 2.6Hz, 1H), 7.18 (d, J = 8.88 Hz, 1H), 4.37- 4.22 (m, 4H), 2.25 (s, 3H)150FB

MS (ESI) m/z 539 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H),9.03 (s, 1H), 7.25 (d, J = 2.6 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H),7.63-7.67 (m, 2H), 7.50 (d, J = 6.5 Hz, 1H), 7.41- 7.44 (m, 1H), 7.41 (dd, J= 2.8 Hz, J'= 2.6 Hz, 1H), 4.36 (s, 4H), 4.41-4.48 (m, 1H), 2.24 (s,3H), 1.19 (d, J = 6.2 Hz, 6H) 150FC

MS (ESI) m/z 472 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.9 (s, 1H), 8.62(d, J = 5.2 Hz, 1H), 7.91 (d, J = 5.16 Hz, 1H), 7.63-7.72 (m, 2H),7.40-7.44 (m, 3H), 7.24 (d, J = 2.64 Hz, 1H), 7.19 (d, J = 8.84, 1H),4.33-4.37 (m, 4H), 2.28 (s, 3H) 151

MS (ESI) m/z 696.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.69 (bs,1H), 68.92 (d, J = 4.4 Hz, 1H), 6 8.34 (s, 1H), 6 8.09 (s, 1H), 67.63-7.57 (m, 2H), 67.45 (d, J = 2.0 Hz, 1H), 6 7.36 (d, J = 8.8 Hz,1H), 6 4.42 (t, 4.8 Hz, 2H), 6 4.24 (t, J = 4.8, 2H), 6 3.56 (s, 3H), 61.65 (s, 3H) 152

MS (ESI) m/z 579.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.96 (b, 1H),8.74(d, J = 4.72 Hz, 1H), 8.62 (s, 1H), 8.13 (d, J = 9.76 Hz, 1H), 7.76(d, J = 9.76 Hz, 1H), 7.68 (t, J = 2.04 Hz, 1H), 7.53 (d, J = 4.72 Hz,1H), 7.3 (t, J = 53.68 Hz, 1H), 4.88 (s, 2H), 2.22(s, 3H) 155

MS (ESI) m/z 485.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.89 (bs,1H), 9.17 (s, 1H), 9.00 (s, 1H), 7.88 (m, 1H), 7.46-7.36 (m, 3H),7.16-7.12 (m, 2H), 4.32 (bs, 4H), 3.67 (s, 1H), 1.98 (s, 3H) 157

MS (ESI) m/z 511.48 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H),9.23 (s, 1H), 7.88-7.86 (dd, J = 1.28, J = 6.8 Hz, 1H), 7.80 (d, J = 1.6Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.45-7.17 (m, 5H), 4.36 (s, 4H), 2.19(s, 3H) 183

MS (ESI) m/z 690.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H),8.79 (d, J = 4.8 Hz, 1H), 8.59 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.46 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.38 (d, J = 9.0 Hz,1H), 4.89 (dt, J = 47.1, 4.7 Hz, 2H), 4.44-4.33 (m, 3H), 4.23 (t, J =5.1 Hz, 2H), 3.93 (hept, J = 6.8 Hz, 1H), 3.79-3.52 (m, 7H), 1.87 (s,3H), 1.25 (d, J = 6.8 Hz, 6H) 184

MS (ESI) m/z 561.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H),9.08 (s, 1H), 8.32 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.39-7.16 (m, 5H),4.34 (d, J = 3.6 Hz, 6H), 3.25-3.18 (m, 3H), 2.89 (s, 2H), 1.42 (d, J =15 Hz, 4H), 1.27- 1.18 (m, 2H) 260

MS (ESI) m/z 636.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H),8.82 (d, J = 4.9 Hz, 1H), 8.40 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 4.40 (t, J = 5.0 Hz, 2H), 4.25 (t, J = 5.0 Hz, 2H), 3.50- 3.41 (m,1H), 2.24-1.94 (m, 8H), 1.83 (s, 3H) 284

MS (ESI) m/z 636.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H),8.80 (d, J = 4.8 Hz, 1H), 8.60 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H),7.49 (d, J = 4.8 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 4.42 (t, J = 4.9 Hz, 2H), 4.25 (t, J = 4.9 Hz, 2H), 3.94- 3.82 (m,1H), 2.23-1.94 (m, 6H), 1.86 (td, J = 12.7, 12.1, 4.2 Hz, 2H), 1.80 (s,3H) 338

MS (ESI) m/z 560.1 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) d/ppm = 8.89 (s,1H), 8.49 (s, 1H), 7.59 (dd, J = 8.9, 2.6 Hz, 1H), 7.43- 7.41 (m, 2H),7.36 (d, J = 8.9 Hz, 1H), 4.43 (t, J = 4.8 Hz, 2H), 4.26 (t, J = 4.8 Hz,2H), 3.19 (q, J = 7.5 Hz, 2H), 2.69 (s, 3H), 1.93 (s, 3H), 1.27 (t, J =7.5 Hz, 3H) 339

MS (ESI) m/z 572.1; 1H-NMR (400 MHz, d6- DMSO) d/ppm = 8.77 (s, 1H),8.59 (s, 1H), 7.59 (dd, J = 8.9, 2.6 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H),7.41 (s, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.42 (t, J = 5.0 Hz, 2H), 4.27(t, J = 5.0 Hz, 2H), 3.21-3.11 (m, 1H), 2.68 (s, 3H), 1.92 (s, 3H),1.33-1.26 (m, 1H), 1.21-1.15 (m, 1H) 340

MS (ESI) m/z 600.2 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) d/ppm = 9.11 (s,1H), 8.63 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.46- 7.44 (m, 2H),7.36 (d, J = 8.9 Hz, 1H), 4.44 (t, J = 4.9 Hz, 2H), 4.30 (t, J = 4.9 Hz,2H), 2.70 (s, 3H), 2.05 (s, 3H) 365

MS (ESI) m/z 603.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H),8.96 (s, 1H), 8.34 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (s,1H), 7.41 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.41 (t, J =5.0 Hz, 2H), 4.28 (t, J = 5.1 Hz, 2H), 3.69-3.61 (m, 2H), 3.58-3.50 (m,2H), 2.93 (s, 3H), 2.92 (s, 3H), 2.72 (s, 3H), 1.92 (s, 3H) 372

MS (ESI) m/z 582.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H),8.59 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.52 (t, J = 53.5 Hz, 1H),7.44 (d, J = 2.6 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 4.42(t, J = 5.0 Hz, 2H), 4.27 (t, J = 5.0 Hz, 2H), 2.66 (s, 3H), 1.90 (s,3H) 384

MS (ESI) m/z 552.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.62 (s, 1H), 7.80-7.73 (m, 1H), 7.72- 7.65(m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.86 (s, 2H), 2.67-2.61 (m, 1H), 2.09(s, 3H), 1.29- 1.15 (m, 4H) 385

MS (ESI) m/z 649.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H),8.84 (s, 1H), 8.56 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s,1H), 7.40 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.41 (t, J =5.1 Hz, 2H), 4.25 (t, J = 5.1 Hz, 2H), 3.57 (s, 3H), 2.68 (s, 3H), 2.61(tt, J = 7.6, 4.9 Hz, 1H), 1.87 (s, 3H), 1.31-1.13 (m, 4H) 400

MS (ESI) m/z 644.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H),7.59 (dd, J = 8.9, 2.6 Hz, 1H), 7.44-7.38 (m, 2H), 7.37 (d, J = 9.0 Hz,1H), 4.42 (t, J = 5.0 Hz, 2H), 4.25 (t, J = 5.0 Hz, 2H), 3.87-3.78 (m,2H), 3.26 (td, J = 11.7, 2.1 Hz, 2H), 2.96 (d, J = 7.1 Hz, 2H), 2.73 (s,3H), 2.69 (s, 3H), 2.15-2.02 (m, 1H), 1.92 (s, 3H), 1.56-1.47 (m, 2H),1.33 (qd, J = 12.0, 4.4 Hz, 2H) 418

MS (ESI) m/z 572.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H),8.42 (s, 1H), 7.59 (dd, J = 8.8, 2.6 Hz, 1H), 7.42 (s, 1H), 7.41 (d, J =2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.25(t, J = 5.0 Hz, 2H), 2.70 (s, 3H), 2.65-2.56 (m, 1H), 1.86 (s, 3H),1.27-1.14 (m, 4H) 419

MS (ESI) m/z 546.7 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H),8.38 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (s, 1H), 7.41 (d, J =2.6 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.25(t, J = 5.0 Hz, 2H), 2.79 (s, 3H), 2.71 (s, 3H), 1.88 (s, 3H) 420

MS (ESI) m/z 588.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H),8.46 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J =2.5 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.39 (t, J = 5.1 Hz, 2H), 4.24(t, J = 5.1 Hz, 2H), 2.71 (s, 3H), 1.86 (s, 3H), 1.58 (s, 9H) 432

MS (ESI) m/z 574.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H),8.42 (s, 1H), 7.59 (dd, J = 8.9, 2.6 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H),7.42 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 4.39 (t, J = 4.9 Hz, 2H), 4.25(t, J = 5.0 Hz, 2H), 3.64 (hept, J = 6.8 Hz, 1H), 2.70 (s, 3H), 1.87 (s,3H), 1.33 (d, J = 6.7 Hz, 6H) 435

MS (ESI) m/z 587.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.52-8.47 (m,2H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.40-7.35 (m, 2H), 7.31 (d, J = 9.0Hz, 1H), 4.37-4.29 (m, 6H), 4.16 (t, J = 5.1 Hz, 3H), 2.68 (s, 3H),2.40- 2.28 (m, 2H), 1.79 (s, 3H) 441

MS (ESI) m/z 655.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J =2.7 Hz, 1H), 8.48 (s, 1H), 8.06 (dd, J = 9.1, 2.8 Hz, 1H), 7.60 (dd, J =8.9, 2.7 Hz, 1H), 7.49-7.34 (m, 3H), 4.46 (t, J = 5.0 Hz, 2H), 4.30 (t,J = 5.1 Hz, 2H), 2.79 (s, 3H), 2.72 (s, 3H), 2.35 (s, 3H), 2.00 (s, 3H)448

MS (ESI) m/z 630.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H),8.82 (d, J = 4.8 Hz, 1H), 8.48 (s, 1H), 7.61 (dd, J = 9.0, 2.7 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.41-7.37 (m, 2H), 4.43 (t, J = 5.1 Hz, 2H),4.33 (d, J = 14.1 Hz, 2H), 4.24 (t, J = 5.1 Hz, 2H), 3.60 (d, J = 11.9Hz, 2H), 3.33-3.19 (m, 2H), 2.91 (d, J = 3.1 Hz, 3H), 2.66 (s, 3H), 1.89(s, 3H) 450

MS (ESI) m/z 638.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H),8.64 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.4, 2.2 Hz, 1H),7.63 (d, J = 2.1 Hz, 1H), 7.46 (s, 1H), 4.81 (s, 2H), 4.35 (d, J = 14.1Hz, 2H), 3.62 (d, J = 12.0 Hz, 2H), 3.48-3.23 (m, 6H), 2.92 (d, J = 3.5Hz, 3H), 2.74 (s, 3H), 2.66 (s, 3H), 2.17 (s, 3H) 459

MS (ESI) m/z 560.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J =4.8 Hz, 1H), 8.63 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.72- 7.63 (m, 2H),7.53 (d, J = 4.8 Hz, 1H), 4.85 (s, 2H), 2.78 (d, J = 10.6 Hz, 6H), 2.15(s, 3H) 474

LCMS: 640.2 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H),7.99-7.89 (m, 2H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.48-7.31 (m, 5H),4.45 (t, J = 5.0 Hz, 2H), 4.28 (t, J = 5.1 Hz, 2H), 2.79 (s, 3H), 2.71(s, 3H), 1.97 (s, 3H) 475

LCMS: 640.2 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H),7.79-7.68 (m, 2H), 7.66-7.57 (m, 2H), 7.45-7.34 (m, 4H), 4.45 (t, J =5.1 Hz, 2H), 4.29 (t, J = 5.0 Hz, 2H), 2.80 (s, 3H), 2.71 (s, 3H), 1.99(s, 3H) 476

LCMS: 640.2 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.72(td, J = 7.7, 1.9 Hz, 1H), 7.67-7.57 (m, 2H), 7.47-7.34 (m, 5H), 4.44(t, J = 5.0 Hz, 2H), 4.28 (t, J = 5.0 Hz, 2H), 2.80 (s, 3H), 2.71 (s,3H), 1.96 (s, 3H) 477

LCMS: 636.7 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H),7.81-7.75 (m, 2H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.46-7.32 (m, 5H),4.45 (t, J = 5.0 Hz, 2H), 4.28 (t, J = 5.1 Hz, 2H), 2.78 (d, J = 0.7 Hz,3H), 2.71 (s, 3H), 2.42 (s, 3H), 1.94 (s, 3H) 478

LCMS: 636.8 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H),7.70-7.63 (m, 2H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.48-7.33 (m, 5H),4.45 (t, J = 5.0 Hz, 2H), 4.28 (t, J = 5.0 Hz, 2H), 2.79 (s, 3H), 2.71(s, 3H), 2.43 (s, 3H), 1.94 (s, 3H) 479

LCMS: 636.8 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.60(dd, J = 8.9, 2.7 Hz, 1H), 7.44 (dq, J = 3.9, 2.0 Hz, 4H), 7.42- 7.31(m, 3H), 4.44 (t, J = 5.0 Hz, 2H), 4.28 (d, J = 4.9 Hz, 2H), 2.77 (s,3H), 2.71 (s, 3H), 2.18 (s, 3H), 1.90 (s, 3H) 480

LCMS: 656.4 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.92 (d,J = 2.1 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.68-7.63 (m, 2H), 7.60 (dd,J = 8.9, 2.7 Hz, 1H), 7.45-7.36 (m, 3H), 4.45 (t, J = 5.0 Hz, 2H), 4.29(t, J = 4.9 Hz, 2H), 2.79 (s, 3H), 2.70 (s, 3H), 1.97 (s, 3H) 481

LCMS: 656.6 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.94(td, J = 1.9, 0.6 Hz, 1H), 7.85 (dt, J = 7.1, 1.7 Hz, 1H), 7.67- 7.57(m, 3H), 7.45-7.36 (m, 3H), 4.46 (t, J = 5.1 Hz, 2H), 4.29 (t, J = 5.0Hz, 2H), 2.79 (s, 3H), 2.72 (s, 3H), 1.99 (s, 3H) 482

LCMS: 656.7 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H),7.70-7.63 (m, 2H), 7.62-7.52 (m, 3H), 7.46-7.41 (m, 2H), 7.38 (d, J =9.0 Hz, 1H), 4.44 (t, J = 5.0 Hz, 2H), 4.28 (s, 2H), 2.79 (s, 3H), 2.71(s, 3H), 1.94 (s, 3H) 491

MS (ESI) m/z 574.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H),8.59 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.50-7.41 (m, 2H), 7.35(d, J = 9.0 Hz, 1H), 4.42 (t, J = 5.0 Hz, 2H), 4.26 (t, J = 5.1 Hz, 2H),4.12-4.00 N (m, 1H), 2.68 (s, 3H), 1.94 (s, 3H), 1.26 (d, J = 6.8 Hz,6H) 492

MS (ESI) m/z 560.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H),7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.42-7.35 (m, 4H), 4.43 (t, J = 5.1 Hz,2H), 4.26 (t, J = 5.1 Hz, 2H), 2.72 (d, J = 3.2 Hz, 6H), 2.70 (s, 3H),1.96 (s, 3H) 597

MS (ESI) m/z 532.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.0 (d, J =5.6 Hz, 1H), 8.38 (s, 1H), 7.59 (dd, J = 8.8, 2.5 Hz, 1H), 7.41 (d, J =2.1 Hz, 2H), 7.35 (d, J = 9.0 Hz, 1H), 4.4 (t, J = 4.2 Hz, 2H), 4.26 (t,J = 4.8 Hz, 2H), 2.7 (s, 3H), 1.85 (s, 3H) 600

MS (ESI) m/z 609.11 [M + 1; 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H),9.01 (d, J = 5.44, 1H), 8.51 (s, 1H), 7.62-7.56 (m, 1H), 7.49-7.31 (m,3H), 4.41 (s, 2H), 4.26 (s, 2H), 3.58 (s, 3H), 2.69 (s, 3H), 1.91 (s,3H) 601

MS (ESI) m/z 526.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H),9.08 (s, 1H), 8.61 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.69-7.66 (m, 2H),7.46 (s, 1H), 4.87 (s, 2H), 2.61 (s, 3H), 2.16 (s, 3H) 602

MS (ESI) m/z 598.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H),8.40 (s, 1H), 7.85 (t, J = 72.0 Hz, 1H), 7.59 (d, J = 8.92 Hz, 1H), 7.42(bs, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.40 (t, J = 5.12 Hz, 2H), 4.25 (t,J = 4.44 Hz, 2H), 2.71 (s, 3H), 1.82 (s, 3H) 603

MS (ESI) m/z 642.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H),8.82 (d, J = 4.8 Hz, 1H), 8.53 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.7 Hz 1H), 7.39 (d, J = 9.0 Hz1H), 4.55- 4.38 (m, 3H), 4.30-4.15 (m, 2H), 3.66-3.44 (m, 4H), 3.27-3.12(m, 1H), 3.05-2.83 (m, 4H), 2.64 (s, 3H), 1.85 (s, 3H), 1.44-1.22 (m,2H) 604

MS (ESI) m/z 598.18 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.66 (s ,1H),8.54 (s, 1H), 7.82 (t, J = 71.4 Hz, 1H), 7.60 (dd, J = 2.52, 8.84 Hz,1H), 7.42 (d, J = 2.5 Hz, 1H), 7.40 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H),4.42 (t, J = 5.46 Hz, 2H), 4.29 (t, J = 5.46 Hz, 2H), 2.71 (s, 3H), 2.01(s, 3H) 624

MS (ESI) m/z 512.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H),9.06 (s, 1H), 8.74 (d, J = 4.76 Hz, 1H), 8.61 (s, 1H), 7.76 (d, J =8.96, 1H), 7.70-7.65 (m, 2H), 7.54 (d, J = 4.76, 1H), 4.87 (s, 2H), 2.13(s, 3H) 656

MS (ESI) m/z 636.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, OH),8.78 (d, J = 4.8 Hz, 1H), 8.67 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.69(dd, J = 8.3, 2.2 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 4.8Hz, 1H), 4.91- 4.76 (m, 2H), 4.57 (d, J = 14.5 Hz, 1H), 3.73- 3.12 (m,4H), 3.08-2.87 (m, 4H), 2.71 (s, 3H), 2.10 (s, 3H), 1.51 (s, 1H),1.41-1.29 (m, 1H) 673

LCMS (ESI) m/z 546.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H),8.44 (s, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.41-7.35 (m, 2H), 7.33(d, J = 9.0 Hz, 1H), 4.40 (s, 2H), 4.23 (s, 2H), 2.72 (s, 3H), 2.67 (s,3H), 1.88 (s, 3H) 674

LCMS (ESI) m/z 531.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H),8.82 (dd, J = 4.8, 1.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 7.64- 7.56 (m,1H), 7.52-7.40 (m, 2H), 7.36 (dd, J = 9.0, 4.8 Hz, 1H), 4.43 (t, J = 5.0Hz, 2H), 4.25 (t, J = 4.9 Hz, 2H), 2.76 (s, 3H), 1.85- 1.78 (m, 3H) 707

MS (ESI) m/z 616.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 7.60 (dd, J = 8.9,2.7 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.37(d, J = 9.0 Hz, 1H), 4.40 (t, J = 4.9 Hz, 2H), 4.32 (d, J = 14.2 Hz,2H), 4.24 (t, J = 5.0 Hz, 2H), 3.61 (d, J = 12.0 Hz, 2H), 3.45 (t, J =13.1 Hz, 2H), 3.32- 3.21 (m, 2H), 2.91 (d, J = 3.5 Hz, 3H), 1.84 (s, 3H)721

MS (ESI) m/z 560.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.73 (bs,1H), 8.85 (s, 1H), 7.68 (s, 1H), 7.47 (dd, J = 2.64, 8.88 Hz, 1H), 7.28(d, J = 2.60 Hz, 1H), 7.24 (d, J = 8.88 Hz, 1H), 7.19 (d, J = 8.00 Hz,1H), 6.98 (d, J = 8.16 Hz, 1H), 4.34 (t, J = 4.60 Hz, 2H), 4.24 (t, J =4.32 Hz, 2H), 3.93 (s, 3H), 2.79 (s, 3H), 1.86 (s, 3H) 722

MS (ESI) m/z 544.96 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H),8.84 (s, 1H), 7.92 (s, 1H), 7.49 (dd, J = 2.48 Hz, J = 8.84 Hz, 1H),7.28-7.24 (m, 3H), 7.13 (d, J = 7.32 Hz, 1H), 4.35 (t, J = 4.56 Hz, 2H),4.21 (t, J = 4.48 Hz, 2H), 2.79 (s, 3H), 2.67 (s, 3H), 1.76 (s, 3H) 723

MS (ESI) m/z 564.90 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.15 (bs,1H), 8.52 (s, 1H), 7.97 (s, 1H), 7.53-7.48 (m, 2H), 7.34 (d, J = 2.4Hz ,1H), 7.28 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 4.36 (t, J =4.44 Hz, 2H), 4.22 (t, J = 4.4 Hz, 2H), 2.81 (s, 3H), 1.79 (s, 3H) 725

MS (ESI) m/z 574 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.92 (bs, 1H),8.35 (s, 1H), 7.96 (s, 1H), 7.49 (dd, J = 8.84, 2.48 Hz, 1H), 7.27- 7.21(m, 3H), 7.12 (d, J = 7.32 Hz, 1H), 4.33 (t, J = 4.56 Hz, 2H), 4.17 (t,J = 4.44 Hz, 2H) 3.41 (s, 6H), 2.65 (s, 3H), 1.67 ( s, 3H) 726

MS (ESI) m/z 560.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H),8.58 (s, 1H), 7.94 (s, 1H), 7.48 (dd, J = 8.88, 2.64 Hz, 1H), 7.28-7.22(m, 3H), 7.37 (d, J = 7.36 Hz, 1H), 4.34 (s, 2H), 4.20 (s, 2H), 4.09 (s,3H), 2.67 (s, 3H), 1.80 (s, 3H) 727

MS (ESI) m/z 574.98 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H),8.96 (s, 1H), 7.93 (s, 1H), 7.48 (dd, J = 8.88, 2.56 Hz, 1H), 7.28-7.24(m, 3H), 7.12 (d, J = 7.36, 1H), 4.95 (s, 2H), 4.34 (t, J = 4.4 Hz, 2H),4.20 (t, J = 4.84 Hz, 2H), 3.41 (s, 3H), 2.66 (s, 3H), 1.74 (s, 3H) 728

MS (ESI) m/z 595.96 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H)7.60 (dd, J = 8.88, 2.76 1H), 7.42-7.08 (m, 4H), 4.43 (t, J = 4.68 Hz,2H), 4.27 (t, J = 4.44 Hz, 2H), 2.79 (s, 3H), 2.70 (s, 3H), 1.91 (s, 3H)730

MS (ESI) m/z 614.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (bs,1H), 8.48 (s, 1H), 7.59 (d, J = 8.72 Hz, 1H), 7.42 (d, J = 4.8 Hz, 2H),7.37 (d, J = 8.8 Hz, 1H), 4.44 (bs, 2H), 4.29 (bs, 2H), 2.80 (s, 3H),2.71 (s, 1H), 1.94 (s, 1H 731

MS (ESI) m/z 622.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H),8.83 (s, 1H), 8.63 (s, 1H), 7.61 (dd, J = 2.44, 8.84 Hz, 1H), 7.45(s,1H), 7.39 (d, J = 9.4 Hz, 2H), 4.43 (t, J = 4.48 Hz, 2H), 4.28 (t, J= 4.6 Hz, 2H), 3.56 (s, 3H), 2.75 (s, 3H), 2.69 (s, 3H), 2.01 (s, 3H)732

MS (ESI) m/z 616.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 at hightemperature) 6 8.96 (s, 1H), 8.75 (s, 1H), 7.56-7.52 (dd, J = 6.4 Hz,9.2 Hz, 1H), 7.38 (d, J = 2.8 Hz, 1H), 7.36 (s, 1H), 7.27 (bs, 1H), 4.43(t, J = 5.2 Hz, 2H), 4.28 (t, J = 4.8 Hz, 2H), 2.73 (s, 3H), 2.63 (s,3H), 2.00 (s, 3H) 733

MS (ESI) m/z 599.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H),8.11 (s, 1H), 7.55-7.52 (dd, J = 2.4, 8.8 Hz, 1H), 7.41 (d, J = 2.4 Hz,1H), 7.31 (d, J = 9.2 Hz, 1H), 7.19 (s, 1H), 5.74-5.69 (m, 1H), 4.38 (t,J = 4.4 Hz, 2H), 4.26 (t, J = 4.4 Hz, 2H), 2.79 (s, 3H), 2.57 (s, 3H),1.79 (s, 3H) 734

MS (ESI) m/z 644.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H),7.59 (dd, J = 8.88, 2.44 Hz, 1H), 7.41 (s, 2H), 7.36 (d, J = 8.96, 1H),4.42 (t, J = 4.52 Hz, 2H), 4.25 (t, J = 4.4 Hz, 2H), 3.79 (t, J = 10.28Hz, 2H), 3.26 (t, J = 11.36 Hz, 2H), 2.96 (d, J = 6.92 Hz, 2H), 2.73 (s,3H), 2.69 (s, 3H), 2.09 (bs, 1H), 1.92 (s, 3H), 1.51 (d, J = 11.16 Hz,2H), 1.39-1.28 (m, 2H) 737

MS (ESI) m/z 622.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.51 (bs,1H), 8.50 (s, 1H), 7.55 (bs, 2H), 7.64-7.7.45 (m, 4H), 7.42-7.36 (m,3H), 4.44 (bs, 2H), 4.28 (bs, 2H), 2.78 (s, 3H), 2.69 (s, 3H), 1.94 (s,3H) 742

MS (ESI) m/z 586.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6): 6 13.5 (bs,1H), 8.49 (s, 1H), 7.60-7.57 (dd, J = 2.4, 8.8 Hz, 1H), 7.39-7.35 (m,3H), 4.42 (t, J = 4.4 Hz, 2H), 4.25 (t, J = 3.6 Hz), 2.68 (s, 3H), 2.66(s, 3H), 1.90 (s, 3H), 1.18-1.16 (m, 4H) 749

MS (ESI) m/z 668.00 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 611.6 (bs, 1H),8.86 (s, 1H), 8.47 (s, 1H), 7.58-7.55 (m, 1H), 7.51 (d, J = 2.4 Hz, 1H),7.39 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 4.41 (t, J = 4.8 Hz, 2H), 4.27(t, J = 5.20 Hz, 2H), 2.77 (s, 3H), 2.59 (s, 3H), 1.73 (s, 3H) 756

MS (ESI) m/z 541.2 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.42 (bs, 1H),9.11 (bs, 1H), 8.89 (s, 1H), 7.76 (d, J = 2.16 Hz, 1H), 7.74-7.62 (m,2H), 7.53-7.38 (m, 2H), 7.11 (t, J = 7.80 Hz, 1H), 4.46 (s, 2H), 4.23(s, 2H), 2.62- 2.57 (m, 1H), 1.89 (s, 3H), 1.29-1.08 (m, 4H) 757

MS (ESI) m/z 548.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.54 (bs,1H), 9.02 (s, 1H), 8.44 (d, J = 4.8 Hz 1H), 7.45 (dd, J = 2.8, 8.8 Hz,1H), 7.26-7.20 (m, 3H), 4.31 (s, 4H), 2.62- 2.58 (m, 1H), 2.02 (s, 3H),1.93 ( s, 3H), 1.20 (d, J = 8.0 Hz ,2H), 1.12 (s, 2H) 762

MS (ESI) m/z 607.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H),9.16 (s, 1H), 8.84 (d, J = 5.80, 2H), 7.91 (d, J = 5.92 Hz, 2H), 7.80(s, 1H), 7.50 (dd, J = 8.84, 2.56 Hz, 1H), 7.29-7.26 (m, 3H), 7.15 (d, J= 7.32 Hz, 1H), 4.36 (t, J = 5.64, 2H), 4.25 (t, J = 3.80, 2H), 2.68 (s,3H), 1.79 (s, 3H) 763

MS (ESI) m/z 622.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.9 (bs, 1H),9.19 (s, 1H), 8.76 (d, J = 5.24, 1H), 7.89 (s, 1H), 7.85 (s, 1H), 7.77(s, 1H), 7.51 (dd, J = 8.84, 2.52 Hz, 1H), 7.29-7.26 (m, 3H), 7.15 (d, J= 7.32 Hz, 1H), 4.36 (t, J = 3.96 Hz, 2H), 4.25 (t, J = 4.96 Hz 2H),2.68 (s, 3H), 2.65 (s, 3H), 1.78 (s, 3H) 770

MS (ESI) m/z 588.72 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H),8.88 (d, J = 5.64 Hz, 2H), 8.79 (d, J = 4.76 Hz, 1H), 8.63 (s, 1H), 8.00(d, J = 5.72 Hz, 2H), 7.77 (d, J = 8.08 Hz, 1H), 7.70-7.68 (m, J = 8.0Hz, 2H) 7.55 (d, J = 4.76 Hz, 1H), 4.89 (s, 2H), 2.22 (s, 3H) 771

MS (ESI) m/z 585.00 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.94 (bs,1H), 8.94 (s, 1H), 7.76 (s, 1H), 7.48 (dd, J = 2.52, 8.76 Hz, 1H),7.26-7.24 (m, 2H), 7.06 (s, 1H), 4.32 (t, J = 4.48 Hz, 2H), 4.20 (t, J =5.08 Hz, 2H), 2.62- 2.59 (m, 1H), 2.49 (s, 3H), 2.33 (s, 3H), 1.75 (s,3H), 1.22 (bs, 2H), 1.14 (bs, 2H) 772

MS (ESI) m/z 588.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H),8.70 (d, J = 5.12 Hz, 1H), 7.59 (dd, J = 8.88, 2.48 Hz, 1H), 7.42- 7.39(m, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.44 (t, J = 4.25 Hz, 2H), 4.29 (t,J = 4.28 Hz, 2H), 3.66 (s, 3H), 2.62-2.59 (m, 1H), 1.87 (s, 3H), 1.24-1.19 (m, 4H) 773

MS (ESI) m/z 590.98 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.16 (bs,1H), 8.98 (s, 1H), 7.83 (s, 1H), 7.53-7.49 (m, 2H), 7.33-7.22 (m, 3H),4.34 (t, J = 4.8 Hz, 2H), 4.22 (t, J = 4.4 Hz, 2H), 2.60-2.58 (m, 1H),1.77 (s, 3H), 1.22-1.15 (m, 4H) 791

MS (ESI) m/z 574.95 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (bs,1H), 8.56 (s, 1H), 8.48 (s, 1H), 7.58 (dd, J = 8.8, 2.48 Hz, 1H), 7.41(d, J = 2.52 Hz, 1H), 7.38 (s, 1H), 7.35 (d, J = 9.4 Hz, 1H), 4.39-4.36(m, 2H), 4.21-4.18 (m, 2H), 3.25 (s, 6H), 2.70 (s, 3H), 1.80 (s, 3H) 792

MS (ESI) m/z 565.91 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H),8.39 (s, 1H), 7.59 (dd, J = 8.84, 2.52 Hz, 1H), 7.42 (s, 2H), 7.34 (d, J= 8.96 Hz, 1H), 4.42-4.37 (m, 2H), 4.29-4.24 (m, 2H), 2.71 (s,3H),.1.81(s, 3H) 793

MS (ESI) m/z 585.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H),8.39 (s, 1H), 7.61 (dd, J = 8.88, 2.68 Hz, 1H), 7.45-7.43 (m, 2H), 7.37(d, J = 8.96 Hz, 1H), 4.41 (t, J = 5.08 Hz, 2H), 4.25 (t, J = 5.24 Hz,2H), 3.02 (q, J = 7.56,7.52 Hz, 2H), 2.67 (bs, 1H), 1.83 (s, 3H), 1.35(t, J = 7.52 Hz, 3H), 1.24-1.19 (m, 4H) 794

MS (ESI) m/z 571.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.00 (bs,1H), 8.94 (s, 1H), 7.80 (s, 1H), 7.50 (dd, J = 8.84, 2.4 Hz, 1H),7.26-7.21 (m, 3H), 7.12 (d, J = 7.32 Hz, 1H), 4.34 (t, J = 4.8 Hz, 2H),4.21 (t, J = 4.44 Hz, 2H), 2.66 (s, 3H), 2.62-2.57 (m, 1H), 1.73 (s,3H), 1.22-1.15 (m, 4H) 807

MS (ESI) m/z 608.7 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H),8.41 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.45-7.40 (m, 2H), 7.35(d, J = 9.0 Hz, 1H), 4.45-4.35 (m, 2H), 4.26 (dtt, J = 14.9, 10.4, 5.0Hz, 2H), 3.54 (td, J = 11.5, 7.9 Hz, 1H), 2.70 (s, 3H), 2.54- 2.44(m,1H), 2.37-2.23 (m, 1H), 1.86 (s, 3H) 809

MS (ESI) m/z 558.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J =0.6 Hz, 1H), 8.41 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (d, J =2.7 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.33-7.24 (m, 1H),6.66 (dd, J = 16.7, 1.9 Hz, 1H), 5.88 (dd, J = 10.6, 1.9 Hz, 1H), 4.40(t, J = 5.1 Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H), 2.70 (s, 3H), 1.83 (s,3H) 813

MS (ESI) m/z 546.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H),8.83 (d, J = 4.9 Hz, 1H), 8.41 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.49 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 4.40 (t, J = 5.0 Hz, 2H), 4.25 (t, J = 5.0 Hz, 2H), 3.11 (q, J =7.5 Hz, 2H), 1.81 (s, 3H), 1.34 (t, J = 7.5 Hz, 3H) 814

MS (ESI) m/z 600.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H),8.82 (d, J = 4.8 Hz, 1H), 8.43 (s, 1H), 7.60 (dd, J = 9.0, 2.6 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 8.9 Hz,1H), 4.40 (t, J = 5.0 Hz, 2H), 4.27 (t, J = 5.0 Hz, 2H), 4.16 (q, J =10.7 Hz, 2H), 1.83 (s, 3H) 815

MS (ESI) m/z 644.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.71 (s, 1H), 8.37 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 4.40 (t, J = 5.0 Hz, 2H), 4.23 (t, J = 5.0 Hz, 2H), 4.20- 4.24 (m,2H), 3.60-3.40 (m, 2H), 3.30 (d, J = 14.1 Hz, 2H), 2.81 (d, J = 4.7 Hz,3H), 1.79 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H) 816

MS (ESI) m/z 644.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J =4.8 Hz, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.46 (s, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H),4.45-4.38 (m, 2H), 4.37- 4.28 (m, 2H), 4.22 (t, J = 5.1 Hz, 2H),3.29-3.08 (m, 4H), 2.96 (d, J = 3.9 Hz, 3H), 1.76 (s, 3H), 1.68 (s, 3H),1.48 (s, 3H) 817

MS (ESI) m/z 660.8 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.8 Hz, 1H), 8.47 (d, J = 9.3 Hz, 2H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.38 (d, J = 9.0 Hz,1H), 4.91 (bs, 2H), 4.78 (bs, 2H), 4.49-4.38 (m, 2H), 4.30- 4.14 (m,2H), 3.55-2.82 (br, 4H), 1.79 (s, 3H), 1.32-0.83 (m, 4H) 818

MS (ESI) m/z 678.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.8 Hz, 1H), 8.49 (s, 1H), 8.40 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.48 (d, J = 4.9 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz,1H), 6.26 (tt, J = 55.6, 4.2 Hz, 1H), 4.49-4.35 (m, 2H), 4.29- 4.12 (m,2H), 3.25-2.72 (m, 8H), 1.75 (s, 3H), 0.64-0.53 (m, 2H) 819

MS (ESI) m/z 617.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =4.8 Hz, 1H), 8.60 (s, 1H), 8.36 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 4.59-4.58 (m, 2H), 4.40 (t, J = 5.1 Hz, 2H), 4.20 (t, J = 5.1 Hz,2H), 3.84-3.76 (m, 1H), 3.66-3.54 (m, 2H), 1.91-1.84 (m, 2H), 1.78 (s,3H), 1.53-1.41 (m, 2H) 820

MS (ESI) m/z 699.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (dd, J =4.9, 0.9 Hz, 1H), 8.71 (s, 1H), 8.42 (d, J = 1.5 Hz, 1H), 7.60 (dd, J =9.0, 2.7 Hz, 1H), 7.50 (dd, J = 4.9, 2.6 Hz, 1H), 7.43 (d, J = 2.6 Hz,1H), 7.36 (d, J = 9.0 Hz, 1H), 5.37-5.27 (m, 1H), 4.39 (t, J = 5.0 Hz,2H), 4.22 (t, J = 5.0 Hz, 2H), 3.43-3.26 (m, 2H), 3.02-2.90 (m, 2H),2.81-2.69 (m, 2H), 2.12-2.01 (m, 2H), 1.90-1.79 (m, 2H), 1.75 (s, 3H)821

MS (ESI) m/z 680.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H),8.85 (d, J = 4.8 Hz, 1H), 8.39 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H),7.50 (d, J = 4.8 Hz, 1H), 7.46 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz,1H), 4.42 (t, J = 5.0 Hz, 2H), 4.29 (t, J = 5.0 Hz, 2H), 4.05 (br, 2H),3.62-3.16 (br, 6H), 2.89 (s, 3H), 1.77 (s, 3H) 822

MS (ESI) m/z 648.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76-8.71 (m,2H), 8.66 (s, 1H), 7.75 (dd, J = 8.0, 0.9 Hz, 1H), 7.71-7.64 (m, 2H),7.54 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.59 (bd, J = 16.5 Hz, 4H), 4.41(s, 4H), 3.08 (br, 1H), 2.09 (s, 3H), 0.81-0.76 (m, 4H) 823

MS (ESI) m/z 706.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.61 (s, 1H), 8.47 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.46 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 6.22 (t, J = 53.9 Hz, 1H), 4.56 (br, 6H), 4.38 (t, J = 5.0 Hz, 2H),4.25 (br, 2H), 4.20 (t, J = 5.0 Hz, 2H), 1.79 (s, 3H), 1.32 (s, 6H) 824

MS (ESI) m/z 678.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.9 Hz, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.51 (d, J = 4.9 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz,1H), 6.26 (tt, J = 55.5, 4.2 Hz, 1H), 4.44-4.37 (m, 2H), 4.26- 4.14 (m,2H), 3.44 (dd, J = 7.8, 6.6, 4.1 Hz, 2H), 3.19-2.84 (m, 6H), 1.74 (s,3H), 0.81 (q, J = 6.6 Hz, 1H), 0.69-0.63 (m, 1H) 825

MS (ESI) m/z 686.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J =4.8 Hz, 1H), 8.57 (s, 1H), 8.44 (s, 1H), 7.57 (dd, J = 8.9, 2.7 Hz, 1H),7.43 (d, J = 4.8 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H), 7.32 (d, J = 9.0 Hz,1H), 4.65 (d, J = 48.5 Hz, 2H), 4.45 (br, 4H), 4.35 (t, J = 5.2 Hz, 2H),4.27 (br, 4H), 4.17 (t, J = 5.2 Hz, 2H), 1.76 (s, 3H), 1.29 (br, 2H),0.97 (br, 2H) 826

MS (ESI) m/z 688.7 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.9 Hz, 1H), 8.61 (s, 1H), 8.48 (s, 1H), 7.64-7.58 (dd, J = 8.9, 2.6 Hz,1H), 7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 4.4 Hz, 1H), 7.36 (d, J =9.0 Hz, 1H), 4.71-4.42 (m, 8H), 4.38 (t, J = 5.2 Hz, 2H), 4.28-4.16 (m,4H), 1.80 (s, 3H), 1.26 (s, 6H) 827

MS (ESI) m/z 718.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.8 Hz, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 7.76 (d, J = 9.0 Hz, 1H),7.71-7.67 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.59-4.47 (m,2H), 4.33- 3.54 (br, 8H), 3.14 (s, 3H), 2.63 (br, 1H), 2.06 (s, 3H) 828

MS (ESI) m/z 710.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.8 Hz, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 7.78-7.74 (m, 1H), 7.71-7.67(m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.53-4.45 (m, 1H), 4.49(d, J = 47.2 Hz, 2H), 4.42-4.36 (m, 1H), 4.31-4.24 (m, 1H), 4.15-4.07(m, 1H), 3.99-3.92 (m, 1H), 3.15 (s, 3H), 2.79-2.40 (m, 4H), 2.06 (s,3H), 1.24 (d, J = 1.9 Hz, 6H) 829

MS (ESI) m/z 682.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.35 (d, J = 9.0 Hz,1H), 4.45 (s, 2H), 4.37 (t, J = 5.1 Hz, 2H), 4.34 (s, 2H), 4.19 (t, J =5.1 Hz, 2H), 3.98-3.87 (m, 1H), 2.76 (s, 3H), 2.69-2.42 (m, 4H), 1.76(s, 3H), 1.10- 0.99 (m, 1H), 0.93-0.72 (m, 4H) 830

MS (ESI) m/z 676.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.8 Hz, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 7.77-7.74 (m, 1H), 7.71-7.66(m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 4.48 (s, 2H), 4.36 (s,2H), 3.99- 3.88 (m, 1H), 2.76 (s, 3H), 2.70-2.42 (m, 4H), 2.08 (s, 3H),1.09-0.99 (m, 1H), 0.92-0.72 (m, 4H) 831

MS (ESI) m/z = 586.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.89(s, 1H), 8.40 (s, 1H), 7.59 (dd, J = 9.0, 2.6, 1H), 7.43-7.41 (m, 2H),7.35 (d, J = 9.0 Hz, 1H), 4.39 (t, J = 5.2 Hz, 2H), 4.39 (t, J = 5.2 Hz,2H), 2.71 (s, 3H), 1.86 (s, 3H), 1.47 (s, 3H), 1.12-1.07 (m, 2H),0.92-0.88 (m, 2H) 837

MS (ESI) m/z = 652.1 [M + 1]+; 1H;-NMR (400 MHz, d6-DMSO) δ/ppm = 8.79(d, J = 4.8 Hz, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 7.57 (dd, J = 8.9, 2.7Hz, 1H), 7.44 (d, J = 4.8 Hz, 1H), 7.38 (d, J = 2.7 Hz, 1H), 7.35 (d, J= 8.9 Hz, 1H), 4.94-4.81 (m, 2H), 4.40 (t, J = 4.6 Hz, 2H), 4.28-4.19(m, 4H), 3.88-3.77 (m, 2H), 1.80 (s, 3H) [remaining CH2-protonspresumably obscured by water-peak] 838

MS (ESI) m/z = 666.4 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.81(d, J = 4.8 Hz, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 7.60 (dd, J = 8.8, 2.7Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.38 (d, J= 8.8 Hz, 1H), 4.85 (bt, J = 12.4 Hz, 2H), 4.42 (t, J = 5.0 Hz, 2H),4.24 (t, J = 5.0 Hz, 2H), 4.24-4.14 (b, 2H), 2.87-2.71 (b, 3H), 1.83 (s,3H), remaining protons appear to be obscured by water peak 839

MS (ESI) m/z = 640.0 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 9.00(s, 1H), 8.38 (s, 1H), 7.59 (dd, J = 8.9, 2.8 Hz, 1H), 7.42 (d, J = 2.8Hz, 1H), 7.41 (s, 1H), 7.35 (d, J = 8.9 Hz, 1H), 4.40 (t, J = 4.9 Hz,2H), 4.26 (t, J = 4.9 Hz, 2H), 2.70 (s, 3H), 1.90 (s, 3H), 1.63-1.58 (m,2H), 1.54-1.48 (m, 2H) 840

MS (ESI) m/z = 696.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.78(d, J = 4.8 Hz, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 7.56 (dd, J = 8.9, 2.7Hz, 1H), 7.42 (d, J = 4.8 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 4.44 (s,4H), 4.34 (t, J = 5.0 Hz, 2H), 4.15 (t, J = 5.0 Hz, 2H), 3.89-3.51 (b),3.12-2.76 (b), 1.73 (s, 3H) 842

MS (ESI) m/z = 610.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm =9.98-9.88 (b, 1H), 8.84 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H),7.75 (d, J = 8.4 Hz, 1H), 7.71-7.65 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H),4.83 (s, 2H), 4.36 (bd, J = 14 Hz, 2H), 3.36-3.24 (m, 2H), 2.91 (s, 3H),2.13 (s, 3H); remaining signals are obscured by water peak 843

MS (ESI) m/z = 712.5 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm =9.98-9.79 (b, 1H), 8.81 (d, J = 4.9 Hz, 1H), 8.52 (s, 1H), 8.49 (s, 1H),7.61 (dd, J = 8.9, 2.8 Hz, 1H), 7.48 (d, J = 4.9 Hz, 1H), 7.42 (d, J =2.8 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 5.21-5.08 (m, 2H), 4.43 (t, J =5.0 Hz, 2H), 4.23 (t, J = 5.0 Hz, 2H), 3.76-3.62 (m, partially obscuredby water peak), 3.38- 3.14 (m, partially obscured by water peak),2.49-2.36 (m, 2H), 2.03-1.93 (m, 2H), 1.83 (s, 3H) 844

MS (ESI) m/z = 712.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm =9.98-9.78 (b, 1H), 8.83 (d, J = 4.9 Hz, 1H), 8.70 (s, 1H), 8.43 (s, 1H),7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.48 (d, J = 4.9 Hz, 1H), 7.41 (d, J =2.7 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 4.41 (t, J = 4.8 Hz, 2H), 4.38-4.28 (m, 2H), 4.24 (t, J = 4.8 Hz, 2H), 3.32-3.21 (m, partially obscuredby water peak), 2.47- 2.33 (m, 2H), 2.02-1.91 (m,2 H), 1.85 (s, 3H);remaining signals obscured by water peak 845

MS (ESI) m/z = 726.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm =10.29-9.70 (b, 1H), 8.83 (d, J = 4.7 Hz, 1H), 8.71 (s, 1H), 8.44 (s,1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.48 (d, J = 4.7 Hz, 1H), 7.42 (d,J = 2.7 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 4.41 (t, J = 4.5 Hz, 2H),4.24 (t, J = 4.5 Hz, 2H), 4.50-3.20 (broad signals, partially obscuredby water peak), 2.99 (bq, J = 11 Hz, 2H), 1.85 (s, 3H), 1.52 (s, 6H) 846

MS (ESI) m/z 631.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H),9.85 (s, 1H), 8.73 (d,J = 8.1 Hz, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.42 (s, 1H), 7.40-7.33 (m, 2H), 5.69 (d, J = 7.2 Hz, 1H), 5.60-5.42 (m,1H), 4.78 (s, 1H), 4.59-4.46 (m, 2H), 4.41 (t, J = 5.2 Hz, 2H), 4.29 (q,J = 5.9, 5.4 Hz, 3H), 3.04-2.96 (m, 3H), 2.71 (s, 3H), 2.54 (d, J = 6.4Hz, 3H), 2.11 (d, J = 22.1 Hz, 3H) 848

MS (ESI) m/z 671.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H),7.56 (dd,J = 8.9, 2.7 Hz, 1H), 7.38-7.29 (m, 4H), 4.61- 4.42 (m, 1H),4.36 (t, J = 5.0 Hz, 2H), 4.20 (t, J = 5.0 Hz, 2H), 3.18-3.09 (m, 2H),3.04 (s, 3H), 2.78 (d, J = 4.6 Hz, 3H), 2.67 (s, 4H), 2.17- 1.94 (m,3H), 1.92 (s, 3H) 850

LCMS: 574.6 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.56(dd, J = 8.9, 2.7 Hz, 1H), 7.40-7.28 (m, 3H), 4.39 (t, J = 5.1 Hz, 2H),4.22 (t, J = 5.0 Hz, 2H), 3.00 (q, J = 7.6 Hz, 2H), 2.70 (s, 3H), 2.66(s, 3H), 1.90 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H) 851

LCMS: 560.4 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 4.8 Hz,1H), 8.46 (s, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (d, J = 4.8 Hz,1H), 7.39 (d, J = 2.7 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 4.39 (t, J =5.0 Hz, 2H), 4.21 (t, J = 5.0 Hz, 2H), 3.01 (q, J = 7.5 Hz, 2H), 2.71(s, 3H), 1.80 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H) 854

MS (ESI) m/z 644.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 4.39 (t, J = 5.0 Hz, 2H), 4.21 (s, 2H), 3.08 (s, 3H), 2.81 (d, J =4.7 Hz, 3H), 2.07 (d, J = 8.4 Hz, 5H), 1.77 (s, 3H) 857

LCMS: 642.7 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.80 (d,J = 4.8 Hz, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz,1H), 7.49-7.34 (m, 3H), 4.43 (t, J = 5.0 Hz, 2H), 4.24 (d, J = 5.0 Hz,2H), 3.35 (t, J = 10.8 Hz, 3H), 2.79 (d, J = 3.4 Hz, 3H), 2.23 (s, 2H),2.08 (d, J = 8.1 Hz, 2H), 1.86 (s, 3H) 860

LCMS: 678.5 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.73 (m, 2H),8.66 (s, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.69 (dd, J = 6.2, 2.3 Hz, 2H),7.54 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.69 (t, J = 4.7 Hz, 4H), 3.30(q, J = 10.2 Hz, 2H), 2.84 (t, J = 4.8 Hz, 4H), 2.07 (s, 3H) 861

LCMS: 712.7 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 4.8 Hz,1H), 8.50 (s, 1H), 8.37 (s, 1H), 7.60 (dd, J = 9.0, 2.7 Hz, 1H), 7.47(d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H),4.69 (s, 1H), 4.43 (t, J = 5.1 Hz, 2H), 4.22 (d, J = 5.1 Hz, 2H), 3.22(s, 1H), 3.13 (s, 3H), 3.04 (d, J = 11.2 Hz, 2H), 2.00-1.81 (m, 1H),1.78 (s, 3H) 862

LCMS: 662.5 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.80 (d,J = 4.8 Hz, 1H), 8.45 (d, J = 9.3 Hz, J = 8.9, 2.7 Hz, 1H), 7.48-7.41(m, 2H), 7.39 (d, J = 9.0 Hz, 1H), 5.50 (s, 1H),J = 11.4 Hz, 1H), 5.02(d, J = 12.3 Hz, 1H), 4.44 (q, J = 4.8 Hz, 2H), J = 5.1 Hz, 2H), 3.85(d, J = 12.3 Hz, 1H), 3.26 (d, J = 1.6 Hz, 3H), 2.87 (d, J = 4.1. 12H),7.61 (dd, 5.38 (s, 1H), 5.10 (d, 4.25 (t, Hz, 3H), 2.20-2.03 (m, 1H),1.80 (s, 3H) 863

LCMS: 670.2 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.51 (s,1H), 8.82- 8.75 (m, 1H), 8.44-8.38J = 8.9, 2.6 Hz, 1H), 7.49 (t, J = 5.0Hz, 1H), 7.44 (dd, J = 9.0, 2.7 Hz, 1H),J = 9.0 Hz, 1H), 5.18 (dq, J =11.7, 5.8 Hz, 1H), 5.05 (s, 1H), 4.44 (q, J = 5.2 Hz, 2H), J = 5.0 Hz,2H), 4.05-3.78 (m, 2H), 3.17 (d, J = 9.9 Hz, 1H), 3.07 (s, 3H), 2.72-J =3.4 Hz, 5H) 864

LCMS: 694.5 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 4.9 Hz,1H), 8.40 (d, J = 2.3 Hz, 2H), 7.58 (dd, J = 8.9, 2.7 Hz, 1H), 7.44 (d,J = 4.8 Hz, 1H), 7.40-7.32 (m, 2H), 6.55 (t, J = 52.5 Hz, 2H), 4.89 (s,1H), 4.48- 4.32 (m, 2H), 4.21 (t, J = 5.3 Hz, 2H), 3.10 (s, 3H), 2.91(s, 4H), 2.33-2.08 (m, 4H), 2.05- 1.88 (m, 3H), 1.74 (s, 3H) 865

LCMS: 712.6 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 4.8 Hz,1H), 8.60 (s, 1H), 8.45 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.48(d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H),4.38 (t, J = 5.0 Hz, 2H), 4.33-4.13 (m, 3H), 3.07 (s, 3H), 2.73-2.52 (m,3H), 2.03-1.82 (m, 2H), 1.77 (d, J = 28.9 Hz, 5H), 1.25 (d, J = 16.2 Hz,1H) 866

LCMS: 694.5 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 4.8 Hz,1H), 8.63 (s, 1H), 8.42 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.47(d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H),6.49 (d, J = 52.7 Hz, 1H), 4.64 (d, J = 15.0 Hz, 1H), 4.39 (t, J = 5.0Hz, 2H), 4.22 (t, J = 5.1 Hz, 2H), 3.09 (s, 3H), 2.94 (s, 3H), 1.76 (s,3H) 868

MS (ESI) m/z 670.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H),8.64 (s, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.38-7.30 (m, 3H), 4.90(s, 2H), 4.36 (t, J = 5.1 Hz, 2H), 4.22 (t, J = 5.1 Hz, 2H), 3.56 (d, J= 12.1 Hz, 2H), 3.30 (t, J = 10.9 Hz, 2H), 2.80 (s, 2H), 2.67 (s, 3H),2.02 (d, J = 2.5 Hz, 4H), 1.93 (s, 3H) 869

LCMS: 1.54 Min, 617.5 [M + H]-; 1H NM:R (400 MHz, DMSO-d6) δ 9.07 (s,1H), 8.80 (s, 1H), 8.72 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.44-7.33 (m, 3H), 5.62 (p, J = 6.2 Hz, 1H), 4.58-4.45 (m, 2H), 4.41 (t,J = 5.1 Hz, 2H), 4.25 (dt, J = 20.4, 5.8 Hz, 4H), 2.71 (s, 3H), 2.54 (s,3H), 2.11 (s, 3H) 871

LCMS (ESI) m/z 654.8 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H),7.57 (dd, J = 8.9, 2.7 Hz, 1H), 7.51-7.39 (m, 3H), 7.34 (d, J = 9.0 Hz,1H), 7.26-7.14 (m, 2H), 4.43 (td, J = 8.9, 7.7, 3.7 Hz, 1H), 4.37 (dd, J= 10.3, 4.5 Hz, 1H), 4.23 (t, J = 5.1 Hz, 2H), 2.75 (s, 3H), 2.68 (s,3H), 2.12 (s, 3H), 1.83 (s, 3H) 872

LCMS (ESI) m/z 650.8 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H),7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.49-7.45 (m, 2H), 7.38 (d, J = 9.0 Hz,1H), 7.30 (dd, J = 8.2, 6.9 Hz, 1H), 7.21-7.16 (m, 2H), 4.45 (t, J = 5.0Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H), 2.77 (s, 3H), 2.72 (s, 3H), 2.00 (s,6H), 1.84 (s, 3H) 873

LCMS (ESI) m/z 637.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H),7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.49-7.43 (m, 2H), 7.38 (d, J = 9.0 Hz,1H), 7.30 (dd, J = 8.2, 6.9 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 4.45 (t,J = 5.0 Hz, 2H), 4.26 (t, J = 4.9 Hz, 2H), 2.77 (s, 3H), 2.72 (s, 3H),2.00 (s, 6H) 874

LCMS (ESI) m/z 656.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H),8.54 (s, 1H), 8.30 (dd, J = 9.3, 5.7 Hz, 1H), 7.66-7.57 (m, 2H),7.48-7.33 (m, 3H), 6.96 (ddd, J = 8.2, 5.8, 2.3 Hz, 1H), 4.43 (t, J =5.0 Hz, 2H), 4.24 (t, J = 5.0 Hz, 2H), 2.72 (d, J = 4.6 Hz, 6H), 1.87(s, 3H) 875

LCMS (ESI) m/z 644.1 [M + 1]+; 1H NMR (400 MHz, Chloroform-d) δ 8.48 (s,1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.42-7.37 (m, 2H),4.42 (d, J = 5.3 Hz, 2H), 4.33 (s, 1H), 4.30 (s, 1H), 4.25 (d, J = 5.0Hz, 2H), 3.61 (d, J = 12.2 Hz, 2H), 3.44 (d, J = 13.6 Hz, 4H), 3.24 (d,J = 11.0 Hz, 1H), 2.92 (d, J = 4.4 Hz, 3H), 2.73 (s, 3H), 2.66 (s, 4H),1.98 (s, 3H) 878

LCMS (ESI) m/z 630.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H),8.44 (s, 1H), 7.57 (dd, J = 8.9, 2.7 Hz, 1H), 7.41-7.31 (m, 2H), 4.39(d, J = 10.4 Hz, 1H), 4.39 (s, 1H), 4.20 (s, 1H), 3.79 (t, J = 4.9 Hz,2H), 3.28 (s, 2H), 2.68 (s, 2H), 2.62 (s, 2H), 1.94 (s, 2H) 882

LCMS (ESI) m/z 634.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H),8.80 (d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H),7.47-7.38 (m, 2H), 7.32 (d, J = 9.0 Hz, 1H), 6.27 (s, 1H), 4.37 (t, J =5.0 Hz, 2H), 4.21 (t, J = 4.9 Hz, 2H), 2.87-2.75 (m, 4H), 2.22 (dq, J =14.1, 6.8 Hz, 2H), 1.75 (s, 3H). 883

LCMS (ESI) m/z 617.1 [M + 1]+.; 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s,1H), 8.47 (d, J = 0.8 Hz, 1H), 7.55 (dd, J = 8.9, 2.7 Hz, 1H), 7.41-7.34 (m, 2H), 7.39-7.28 (m, 2H), 7.44-4.40 (m, 2H), 4.34 (t, J = 5.1 Hz,2H), 4.16 (t, J = 5.1 Hz, 2H), 3.86 (dd, J = 11.5, 4.8 Hz, 2H), 3.73(ddd, J = 11.1, 8.1, 3.4 Hz, 1H), 3.54 (d, J = 11.6 Hz, 1H), 2.67 (s,3H), 2.05-1.94 (m, 1H), 1.90 (s, 2H), 1.76 (s, 3H) 884

LCMS (ESI) m/z 614.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H),8.45 (s, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.39-7.29 (m, 3H), 4.36(t, J = 5.1 Hz, 2H), 4.24 (s, 2H), 4.22 − 4.14 (m, 4H), 2.71 (t, J = 7.7Hz, 2H), 2.68 (s, 3H), 1.86 (s, 3H) 885

LCMS (ESI) m/z 662.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =4.8 Hz, 1H), 8.46 (s, 1H), 7.57 (dd, J = 9.0, 2.6 Hz, 1H), 7.44 (d, J =4.8 Hz, 1H), 7.39-7.32 (m, 2H), 4.98-4.74 (m, 2H), 4.40 (t, J = 5.1 Hz,2H), 4.29 (s, 2H), 4.21 (t, J = 5.1 Hz, 2H), 3.64 (s, 2H), 3.56 (s, 2H),3.47 (s, 2H), 3.31 (s, 2H), 2.66 (s, 3H), 1.86 (s, 3H) 886

LCMS (ESI) m/z 698.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.9 Hz, 1H), 8.54 (s, 1H), 7.60 (dd, J = 8.8, 2.8 Hz, 1H), 7.48 (d, J =4.8 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.41(s, 2H), 4.21 (s, 2H), 3.65 (s, 5H), 3.29 (q, J = 10.2 Hz, 2H), 2.82 (s,4H), 2.64 (s, 3H), 1.80 (s, 3H) 888

LCMS (ESI) m/z 613.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H),8.98 (s, 1H), 8.83 (d, J = 4.8 Hz, 1H), 8.36 (s, 1H), 7.60 (dd, J = 8.9,2.7 Hz, 1H), 7.46 (dd, J = 13.2, 3.7 Hz, 2H), 7.36 (d, J = 9.0 Hz, 1H),6.51 (s, 1H), 4.40 (d, J = 5.3 Hz, 2H), 4.27 (d, J = 5.0 Hz, 2H), 4.14(d, J = 17.9 Hz, 1H), 3.91 (s, 1H), 3.69 (d, J = 11.9 Hz, 1H), 3.35 (s,1H), 2.95 (d, J = 4.5 Hz, 6H), 1.81 (s, 3H) 889

1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.80 (d, J = 4.8 Hz, 1H), 8.37(s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 15.4 Hz, 2H), 7.32 (d, J= 9.0 Hz, 1H), 6.40 (s, 1H), 4.37 (s, 2H), 4.21 (s, 2H), 3.35 (d, J =9.9 Hz, 1H), 2.91 (s, 3H), 2.66 (s, 1H), 1.75 (s, 3H) 890

LCMS (ESI) m/z 469.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H),7.76-7.65 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 6.51 (t, J = 54 Hz, 1H),5.43 (s, 1H), 4.84 (s, 2H), 2.28 (s, 2H), 2.18 (s, 1H), 2.12 (s, 3H) 891

LCMS (ESI) m/z 528.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =4.8 Hz, 1H), 8.69 (s, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.72- 7.64 (m, 2H),7.56 (d, J = 4.8 Hz, 1H), 4.78 (s, 2H), 1.92 (s, 3H) 892

LCMS (ESI) m/z 654.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 610.05 (s, 1H),8.73-8.67 (m, 2H), 8.63 (s, 1H), 7.72 (dd, J = 8.1, 0.8 Hz, 1H),7.73-7.61 (m, 2H), 7.51 (d, J = 4.8 Hz, 1H), 4.78 (s, 2H), 4.74-4.67 (m,1H), 4.64- 4.55 (m, 3H), 4.49 (s, 2H), 4.40 (t, J = 6.9 Hz, 4H), 3.59(d, J = 4.6 Hz, 1H), 3.52 (s, 1H), 2.07 (s, 3H), 1.21 (s, 1H) 893

LCMS (ESI) m/z 672.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75-8.67 (m,2H), 8.63 (s, 1H), 7.72 (dd, J = 8.1, 0.8 Hz, 1H), 7.69-7.61 (m, 2H),7.51 (d, J = 4.8 Hz, 1H), 6.34 (t, J = 52 Hz, 1 H), 4.78 (s, 2H), 4.50(s, 5H), 4.45 (s, 3H), 3.81 (s, 1H), 2.94 (s, 2H), 2.35 (s, 6H), 2.07(s, 3H) 894

LCMS (ESI) m/z 720.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.05(s, 1H),8.75-8.71 (m, 2H), 8.66 (s, 1H), 7.78-7.73 (m, 1H), 7.72- 7.64 (m, 2H),7.54 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.65 (s, 2H), 4.52 (s, 2H), 4.44(d, J = 3.7 Hz, 4H), 4.37-4.29 (m, 2H), 3.61 (s, 2H), 2.10 (s, 3H) 895

MS (ESI) m/z 650.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H),8.85 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.69 (dd, J = 8.4, 2.2 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.53(d, J = 4.8 Hz, 1H), 4.84 (s, 2H), 4.38 (d, J = 14.1 Hz, 2H), 3.75 (d, J= 12.0 Hz, 2H), 3.60-3.48 (m, 2H), 3.33-3.23 (m, 2H), 3.17-3.11 (m, 2H),2.14 (s, 3H), 1.18-1.08 (m, 1H), 0.72-0.66 (m, 2H), 0.45-0.37 (m, 2H)897

MS (ESI) m/z 562.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.59 (bs,1H), 8.72 (s, 1H), 8.42 (s, 1H), 7.58 (dd, J = 2.56, 8.72 Hz, 1H), 7.40(bs, 2H), 7.34 (d, J = 8.92 Hz, 1H), 4.39 (t, J = 4.00 Hz, 2H), 4.39 (t,J = 4.52 Hz, 2H), 4.11 (s, 3H), 2.70 (s, 3H), 1.85 (s, 3H) 898

MS (ESI) m/z 586.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.5 (bs, 1H),8.49 (s, 1H), 7.60-7.57 (dd, J = 4.0, 8.8 Hz, 1H), 7.39 (m, 3H), 4.44(t, J = 6.0 Hz, 2H), 4.25 (t, J = 3.6 Hz, 2H), 2.68 (s, 6H), 1.90 (s,3H), 1.18-1.16 (m, 4H) 900

MS (ESI) m/z 572.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.39 (bs,1H), 8.91 (s, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.60-7.57 (dd, J = 7.48,2.56 Hz, 1H), 7.41 (d, J = 2.52 Hz, 1H), 7.33 (d, J = 8.92 Hz, 1H),4.41-4.35 (m, 2H), 4.30-4.20 (m, 2H), 3.01 (s, 3H), 2.67-2.60 (m, 1H),1.81 (s, 3H), 1.28-1.12 (m, 4H) 910

MS (ESI) m/z 648.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.41 (bs,1H), 8.64 (s, 1H), 8.08 (d, J = 3.32 Hz, 2H), 7.58 (dd, J = 2.48, 8.84Hz, 1H), 7.53 (d, J = 2.48 Hz, 3H), 7.42- 7.35 (d, J = 2.48 Hz, 1H),7.35-7.38 (m, 2H), 4.43 (t, J = 5.80 Hz, 2H), 4.28 (t, J = 4.52 Hz, 2H),2.66-2.55 (m, 1H), 2.55 (s, 3H), 1.95 (s, 3H), 1.23 (d, J = 4.28 Hz, 4H)911

MS (ESI) m/z 637.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J =5.2 Hz, 1H), 8.47 (s, 1H), 7.83 (s, 1H), 7.79 (d, J = 4.48 Hz, 1H), 7.60(dd, J = 2.52, 8.84 Hz, 1H), 7.42-7.34 (m, 3H), 4.45 (t, J = 6.12 Hz,2H), 4.30 (t, J = 5.72 Hz, 2H), 2.80 (s, 3H), 2.71 (s, 3H), 2.65 (s,3H), 2.01 (s, 3H) 912

MS (ESI) m/z 586.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H),8.54 (s, 1H), 7.58 (dd, J = 8.92, 2.44 Hz, 1H), 7.42 (d, J = 2.52 Hz,1H), 7.40 (s, 1H), 7.35 (d, J = 8.92 Hz, 1H), 4.95 (t, J = 8.68, 1H),4.41 (t, J = 5.8 Hz, 2H), 4.24 (t, J = 5.84, 2H), 2.68 (s, 3H), 2.37-2.32 (m, 3H), 2.13-2.08 (m, 2H), 1.91 (s, 3H), 1.91 (bs, 2H) 913

MS (ESI) m/z 596.04 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (bs,1H), 9.00 (s, 1H), 8.42 (s, 1H), 7.58 (d, J = 8.68 Hz, 1H), 7.41 (s,2H), 7.35 (d, J = 8.88 Hz, 1H), 4.40 (t, J = 4.88 Hz, 2H), 4.27 (t, J =5.4 Hz, 2H), 2.70 (s, 3H), 2.16 (t, J = 19.28 Hz, 3H), 1.89 (s, 3H) 914

MS (ESI) m/z 582.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H),8.40 (s, 1H), 7.59 (dd, J = 8.8, 2.5 Hz, 1H), 7.43-7.16 (m, 4H), 4.40(t, J = 6.0 Hz, 2H), 4.28 (t, J = 2.6 Hz, 2H), 2.70 (s, 2H), 1.84 (s,3H) 915

MS (ESI) m/z 617.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.53 (bs,1H), 9.02 (s, 1H), 8.36 (s, 1H), 7.59 (dd, J = 8.88 Hz, 2.52 Hz, 1H),7.41-7.39 (m, 2H), 7.34 (d, J = 8.96 Hz, 1H), 5.72 (d, J = 47.16 Hz,2H), 4.40 (t, J = 7.44 Hz, 2H), 4.27 (t, J = 4.48 Hz, 2H), 2.69 (s, 3H),1.88 (s, 3H) 916

MS (ESI) m/z 585.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H),8.39 (s, 1H), 7.61 (dd, J = 8.88Hz, J = 2.68 Hz, 1H), 7.45- 7.43 (m,2H), 7.37 (d, J = 8.96 Hz, 1H), 4.42- 4.39 (m, 2H), 4.26- 4.23 (m, 2H),3.02 (q, J = 7.56 Hz, J = 7.52 Hz, 2H), 2.67 (s, 1H), 1.83 (s, 3H), 1.35(t, J = 7.52 Hz, 3H), 1.24-1.19 (m, 4H) 917

MS (ESI) m/z 590.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H),8.86 (s, 1H), 8.43 (s, 1H), 7.60 (dd, J = 2.48, 8.88 Hz, 1H), 7.51 (s,1H), 7.43 (d, J = 2.52 Hz, 1H), 7.35 (d, J = 8.96, 1H), 5.69 (d, J =46.8 Hz, 2H), 4.40 (t, J = 3.96 Hz, 2H), 4.23 (t, J = 4.40 Hz, 2H),2.61-2.57 (m, 1H), 1.77 (s, 3H), 1.23-1.15 (m, 4H) 922

MS (ESI) m/z 540.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H),8.87 (s, 1H), 7.74 (s, 1H) 7.67 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 8.84,2.40 Hz, 1H), 7.35 (d, J = 8.92 Hz, 1H), 4.44 (s, 4H), 2.68 (s, 3H),2.58-2.57 (m, 1H), 1.20-1.14 (m, 4H) 923

MS (ESI) m/z 560.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H),8.35 (s, 1H), 7.59-7.56 (dd, J = 2.4, 8.4 Hz, 1H), 7.41-7.33 (m, 3H),4.40 (t, J = 4.8 Hz, 2H), 4.26 (t, J = 4.8 Hz, 2H), 3.12 (m, 2H), 2.68(s, 3H), 1.88 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H) 924

MS (ESI) m/z 690 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.4 (s, 1H),8.50 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.89 (t, J = 7.2 Hz, 1H), 7.81(t, J = 8.4 Hz, 1H), 7.61 (dd, J = 2.4, 8.8 Hz, 1H), 7.43 (s, 2H), 7.38(d, J = 8.82 Hz, 1H), 4.44 (bs, 2H), 4.27 (bs, 2H), 2.80 (s, 3H), 2.71(s, 3H), 1.92 (s, 3H) 925

MS (ESI) m/z 690.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H),8.24 (s, 1H), 8.19 (d, J = 7.76 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.84(t, J = 7.8 Hz, 1H), 7.60 (dd, J = 2.56, 8.8 Hz, 1H), 7.43 (s, 1H), 7.39(d, J = 2.2 Hz, 2H), 4.46 (t, J = 3.6 Hz, 2H), 4.30 (t, J = 4.4 Hz, 2H),2.80 (s, 3H), 2.71 (s, 3H), 2.00 (s, 3H) 926

MS (ESI) m/z 690.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.44 (bs,1H), 8.49 (s, 1H), 8.10 (d, J = 8.08 Hz, 2H), 7.95 (d, J = 8.20 Hz, 2H),7.60 (dd, J = 8.88, 2.60 Hz, 1H), 7.43 (s, 1H), 7.42-7.37 (m, 2H), 4.45(t, J = 4.64 Hz, 2H), 4.30 (t, J = 4.36 Hz, 2H), 2.80 (s, 3H), 2.71 (s,3H), 1.99 (s, 3H) 927

MS (ESI) m/z 654.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (bs,1H), 8.48 (s, 1H), 7.60 (dd, J = 2.4, 8.7 Hz, 1H), 7.43-7.37 (m, 5H),7.30-7.26 (m, 1H), 4.44 (t, J = 5.2 Hz, 2H), 4.27 (t, J = 5.8 Hz, 2H),2.77 (s, 3H), 2.71 (s, 3H), 2.13 (s, 3H), 1.93 (s, 3H) 928

MS (ESI) m/z 622.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H),8.35 (s, 1H), 7.58 (dd, J = 2.52, 8.8 Hz, 1H), 7.39 (t, J = 2.68 Hz,2H), 7.35 (d, J = 9 Hz, 1H), 4.39 (t, J = 4.4 Hz, 2H), 4.26 (t, J = 4.28Hz, 2H), 4.04-3.95 (m, 1H), 3.11-3.05 (m, 4H), 2.70 (s, 3H), 1.91 (s,3H) 929

MS (ESI) m/z 636.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.20 (bs,1H), 9.04 (s, 1H), 8.37 (s, 1H), 7.61-7.56 (m, 1H), 7.44-7.38 (m, 2H),7.34 (d, J = 8.96 Hz, 1H), 4.40-4.36 (m, 2H), 4.27-4.15 (m, 3H), 2.68(s, 3H), 2.59-2.56 (m, 1H), 2.32-2.17 (m, 3H), 2.07-2.03 (m, 1H),1.93-1.83 (m, 4H) 930

MS (ESI) m/z 636.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (bs,1H), 8.99 (s, 1H), 8.38 (s, 1H), 7.59 (dd, J = 8.88, 2.52 Hz, 1H),7.40(s, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.41-4.36 (m, 2H), 4.31-4.23 (m,2H), 4.08-4.02 (m, 1H), 2.70 (s, 3H), 2.63-2.57 (m, 2H), 2.38- 2.32 (m,1H), 2.29-2.26 (m, 2H), 2.09-2.05 (m, 1H), 1.91 (s, 3H) 931

MS (ESI) m/z 650.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H),8.35 (s, 1H), 7.59 (dd, J = 8.88, 2.56 Hz, 1H), 7.44-7.40 (m, 2H), 7.35(d, J = 8.96 Hz, 1H), 4.40 (t, J = 4.68 Hz, 2H), 4.25 (t, J = 4.68, 2H),3.60-3.50 (bs, 1H), 2.70 (s, 3H), 2.40-2.21 (m, 2H), 2.20-2.09 (m, 1H),2.00.1.80 (m, 6H), 1.68-1.63 (m, 2H) 940

MS (ESI) m/z 534.16 [M + 1]+;1H NMR (400 MHz, DMSO-d6) δ 13.08 (bs, 1H),8.82 (s, 1H), 7.61-7.56 (m, 2H), 7.36-7.26 (m, 3H), 6.73 (d, J = 7.88Hz, 1H), 4.46-4.30 (m, 4H), 2.60-2.59 (m, merged, 1H), 2.57 (s, 3H),1.28-1.10 (m, 4H) 941

MS (ESI) m/z 626.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.56 (bs,1H), 9.09 (s, 1H), 8.48 (s, 1H), 7.74-7.71 (m, 1H), 7.65-7.58 (m, 2H),7.45-7.34 (m, 4H), 7.35 (d, J = 8.8 Hz, 1H), 4.41 (t, J = 4.60 Hz, 2H),4.28 (t, J = 4.60 Hz, 2H), 2.70 (s, 3H),1.90 (s, 3H) 942

MS (ESI) m/z 626.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (bs,1H), 9.04 (s, 1H), 8.38 (s, 1H), 7.74 (t, J = 6.92 Hz, 2H), 7.67- 7.58(m, 2H), 7.45-7.41 (m, 3H), 7.36 (d, J = 8.76 Hz, 1H), 4.42 (t, J = 4.68Hz, 2H), 4.28 (t, J = 4.08, Hz, 2H), 2.66 (s, 3H), 1.98 (s, 3H) 943

MS (ESI) m/z 626.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (bs,1H), 9.03 (s, 1H), 8.41 (s, 1H), 7.99-7.95 (m, 2H), 7.59 (dd, J = 2.56,8.88 Hz, 1H), 7.45-7.41 (m, 4H), 7.36 (d, J = 8.96 Hz, 1H), 4.42 (t, J =4.76 Hz, 2H), 4.28 (t, J = 4.52 Hz, 2H), 2.70 (s, 3H), 1.90 (s, 3H) 944

MS (ESI) m/z 622.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H),8.43 (s, 1H), 7.60 (dd, J = 8.92 Hz, 2.64 Hz, 1H), 7.47-7.35 (m, 7H),4.42 (t, J = 5.64 Hz, 2H), 4.27 (t, J = 4.4 Hz, 2H), 2.73 (s, 3H), 2.19(s, 3H), 1.86 (s, 3H) 945

MS (ESI) m/z 622.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H),8.41 (s, 1H), 7.90 (s, 1H), 7.68 (s, 1H), 7.58 (dd, J = 8.2, 2.12 Hz,1H), 7.48-7.35 (m, 5H), 4.42 (t, J = 4.48, 2H), 4.27 (t, J = 5.68, 2H),2.71 (s, 3H), 2.43 (s, 3H), 1.88 (s, 3H) 946

MS (ESI) m/z 622.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.5 (s, 1H),9.027 (s, 1H), 8.40 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.58 (dd, J =2.56 Hz, J = 2.52 Hz, 1H), 7.34- 7.42 (m, 5H), 4.40-4.42 (bs, 2H), 4.26-4.28 (bs, 2H), 2.70 (s, 3H), 2.42 (s, 3H), 1.87 (s, 3H) 947

MS (ESI) m/z 642.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.54 (bs,1H), 9.07 (s, 1H), 8.43 (s, 1H), 7.70-7.68 (m, 2H), 7.66-7.54 (m, 3H),7.43-7.42 (m, 2H), 7.35 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 6.16 Hz, 2H),4.27 (t, J = 4.48 Hz, 2H), 2.71 (s, 3H), 1.88 (s, 3H) 948

MS (ESI) m/z 642.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (bs,1H), 9.03 (s, 1H), 8.37 (s, 1H), 7.97 (t, J = 2.0 Hz 1H), 7.90-7.84 (m,1H), 7.67-7.58 (m, 3H), 7.42-7.40 (m, 2H), 7.41 (d, J = 2.6 Hz, 1H),4.42 (t, J = 5.48 Hz, 2H), 4.28 (t, J = 4.40 Hz, 2H), 2.71 (s, 3H), 1.91(s, 3H) 949

MS (ESI) m/z 642.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H),8.40 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.59(dd, J = 8.9, 2.6 Hz, 1H), 7.45-7.40 (m, 2H), 7.36 (d, J = 8.9 Hz, 1H),4.42 (t, J = 8.3 Hz, 2H), 4.28 (t, J = 4.4 Hz, 2H), 2.70 (s, 3H), 1.90(s, 3H) 950

MS (ESI) m/z 676 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H),8.41 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.83(t, J = 8.0 Hz, 2H), 7.61 (dd, J = 2.8, 8.8 Hz, 1H), 7.44 (s, 1H), 7.36(d, J = 9.2 Hz) 1H), 4.42 (bs, 1H), 4.27 (bs, 1H), 2.72 (s, 3H), 1.87(s, 3H) 951

MS (ESI) m/z 676.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H),8.37 (s, 1H), 8.27 (s, 1H), 8.22 (d, J = 7.6 Hz ,1H), 7.96 (d, J = 7.4Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.60 (dd, J = 2.52, 8.8 Hz, 1H), 7.43(s, 1H), 7.41 (d, J = 2.5 Hz ,1H), 7.37 (d, J = 8.9 Hz, 1H), 4.43 (t, J= 5.4 Hz, 2H), 4.29 (t, J = 4.96 Hz, 2H), 2.75 (s, 3H), 1.92 (s, 1H) 952

MS (ESI) m/z 676.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.49 (bs,1H), 9.07 (s, 1H), 8.41 (s, 1H), 8.13 (d, J = 8.16 Hz, 2H), 7.98 (d, J =8.28 Hz, 2H), 7.60 (dd, J = 8.92, 2.60 Hz 1H), 7.43-7.40 (m, 2H), 7.36(d, J = 8.96 Hz 1H), 4.42 (t, J = 6.48 Hz 2H), 4.29 (t, J = 4.48 Hz 2H),2.71 (s, 3H), 1.92 (s, 3H) 953

MS (ESI) m/z 655.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 6, 9.03(s, 1H),8.33 (s, 1H), 7.62-7.58 ( m, 2H), 7.52 (dd, J = 2.16, 8.24 Hz, 1H),7.47-7.42 (m, 3H), 7.37 (d, J = 8.92 Hz, 1H), 4.43 (t, J = 4.96 Hz, 2H),4.29 (t, J = 3.88 Hz, 2H), 2.72 (s, 3H), 2.15 (s, 3H), 1.85 (s, 3H) 954

MS (ESI) m/z 675.95 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H),8.36 (s, 1H), 7.90 (s, 1H), 7.74-7.68 (m, 2H), 7.59 (d, J = 6.6 Hz, 1H),7.42 (s, 2H), 7.35 (d, J = 8.8 Hz, 1H), 4.42 (s, 2H), 4.28 (s, 2H), 2.72(s, 3H), 1.89 (s, 3H) 970

MS (ESI) m/z 521.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.47 (bs,1H), 8.96 (s, 1H), 7.70 (s, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H),7.10 (d, J = 8.8 Hz, 1H), 6.83 (s, 1H), 4.53 (t, J = 6.4 Hz, 2H), 4.39(t, J = 4.8 Hz, 2H), 3.99 (s, 2H), 2.65 (s, 3H), 2.57 (bs, 1H), 1.20 (d,J = 7.6 Hz, 2H), 0.93 (d, J = 6.4 Hz, 2H) 971

MS (ESI) m/z 643.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.38 (bs,1H), 8.63 (s, 1H), 8.46 (s, 1H), 7.59 (dd, J = 2.5, 8.9 Hz, 1H), 7.42(d, J = 2.4 Hz, 1H), 7.36 (s, 1H), 7.34 (s, 1H), 4.76-4.69 (m, 2H), 4.38(t, J = 4.3 Hz, 2H), 4.21 (t, J = 6.2 Hz, 2H), 3.43 (s, 3H), 2.69 (s,3H), 1.81 (s, 3H) 972

MS (ESI) m/z 629.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H),8.43 (s, 1H), 7.77 (t, J = 6.0 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.41(s, 1H), 7.35 (t, J = 5.3 Hz, 2H), 4.37- 4.30 (m, 4H), 4.20 (bs, 2H),2.68 (s, 3H), 1.78 (s, 3H) 973

MS (ESI) m/z 625.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H),8.44 (s, 1H), 7.59 (dd, J = 2.56, 6.28 Hz, 1H), 7.40 (bs, 2H), 7.35 (d,J = 8.96 Hz, 1H), 6.38 (tt, J = 4.08, 59.88 Hz, 1H), 4.38 (t, J = 6.20Hz, 2H), 4.21 (t, J = 4.48 Hz, 2H), 4.16-4.12 (m, 2H), 3.39 (s, 3H),2.71 (s, 3H), 1.84 (s, 3H) 974

MS (ESI) m/z 611.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H),8.47 (s, 1H), 7.60-7.55 (m, 2H), 7.40 (s, 2H), 7.34 (d, J = 8.96 Hz 1H),6.21 (tt, J = 5.28, 57.68 Hz, 1H), 4.36 (t, J = 4.60 Hz, 2H), 4.20 (t, J= 4.60 Hz, 2H), 3.93-3.86 (m, 2H), 2.70 (s, 3H), 1.80 (s, 3H) 975

MS (ESI) m/z 560.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H),8.61 (s, 1H), 7.62-7.59 (dd, J = 2.4, 8.4 Hz, 1H), 7.46 (s, 1H), 7.42(d, J = 2.4 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 4.88 (t, J = 9.6 Hz, 2H),4.40 (t, J = 4.4 Hz, 2H), 4.23 (t, J = 4.8 Hz, 2H), 4.17 (t, J = 9.6 Hz,2H), 3.52 (s, 1H), 2.66 (s, 3H), 1.86 (s, 3H) 976

MS (ESI) m/z 591.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H),8.23 (bs, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.33 (m, 2H),4.37 (t, J = 5.2 Hz, 2H), 4.22 (t, J = 4.0 Hz, 2H), 3.84 (s, 3H), 3.26(s, 3H), 2.66 (s, 3H), 1.63 (s, 3H) 977

MS (ESI) m/z 615.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H),8.44 (s, 1H), 7.59 (dd, J1 = 2.5 Hz, J2 = 8.8 Hz, 1H), 7.41- 7.40 (m,2H), 7.35 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 8.8 Hz, 2H), 4.25 (t, J =9.1 Hz, 2H), 4.08, (t, J = 13.6 Hz, 2H), 2.70 (s, 3H), 2.60-2.58 (m,2H), 2.20 (t, J = 14.3 Hz, 2H), 1.87 (s, 3H) 978

MS (ESI) m/z 604.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H),8.48 (s, 1H), 7.59 (dd, J = 8.8 Hz, 2.48 Hz, 1H), 7.42-7.39 (m, 2H),7.35 (d, J = 8.96 Hz, 1H), 4.37 (d, J = 4.48 Hz, 2H), 4.19 (d, J = 4.8Hz, 2H), 3.05 (s, 3H), 2.70 (s, 3H), 2.53 (s, 6H), 1.78 (s, 3H) 979

MS (ESI) m/z 590.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.69 (bs, 1H),8.57 (s, 1H), 8.46 (s, 1H), 7.59 (dd, J = 8.88 Hz, 2.44 Hz, 1H),7.43-7.41 (m, 2H), 7.34 (d, J = 8.96 Hz, 1H), 4.36 (t, J = 4.28 Hz, 2H),4.18 (t, J = 4.6 Hz, 2H), 2.70 (s, 9H), 1.71 (s, 3H) 980

MS (ESI) m/z 716.23 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =3.60 Hz, 1H), 8.68 (s, 1H), 8.59 (s, 1H), 7.74 (d, J = 8.40 Hz, 1H),7.67-7.64 (m, 2H), 7.43 (d, J = 3.60 Hz, 1H), 4.80 (s, 2H), 4.25 (bs,1H), 3.83 (s, 3H), 3.10 (s, 3H), 3.02 (d, J = 9.6 Hz, 2H), 2.78-2.71 (m,2H), 2.39-2.34 (m, 2H), 2.03 (s, 3H), 1.93- 1.91 (m, 2H), 1.76-1.05 (m,5H) 981

MS (ESI) m/z 554.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H),9.19 (s, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 7.61 (dd, J =2.64, 8.88, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.45 (d, J = 2.68 Hz, 1H),7.37 (d, J = 8.96 Hz, 1H), 6.72-6.46 (t, J = 51.6 Hz, 1H), 4.41 (d, J =4.64 Hz, 2H), 4.36 (d, J = 4.52 Hz, 2H) 982

MS (ESI) m/z 649.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H),8.69 (s, 1H), 8.47 (s, 1H), 7.60 (dd, J = 2.56 Hz, J = 8.88 Hz, 1H),7.42-7.35 (m, 4H), 7.29 (d, J = 7.25 Hz, 1H), 7.12 (t, J = 7.52 Hz, 1H),6.96 (t J = 7.24 Hz, 1H), 4.41 (t, J = 5.04 Hz, 2H), 4.34 (t, J = 8.04Hz, 2H), 4.24 (t, J = 4.76 Hz, 2H), 3.22 (t, J = 7.88 Hz, 2H), 2.71 (s,3H), 1.83 (s, 3H) 983

MS (ESI) m/z 647.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H),8.43 (s, 1H), 7.92 (d, J = 3.36 Hz, 1H), 7.74 (d, J = 8.12 Hz 1H), 7.69(s, J = 7.60 Hz 1H), 7.61 (dd, J = 8.88, 2.48 Hz 1H), 7.45 (s, 1H), 7.43(d, J = 2.48 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.29- 7.20 (m, 2H), 6.84(d, J = 3.28 Hz, 1H), 4.44 (d, J = 4.48 Hz, 2H), 4.29 (d, J = 4.48 Hz,2H), 2.70 (s, 3H), 1.87 (s, 3H) 984

MS (ESI) m/z 598.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H),8.58 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.59 (d, J = 8.76 Hz, 1H),7.42 (s, 2H), 7.35 (d, J = 8.88 Hz, 1H), 6.70 (s, 1H), 4.41 (t, J = 4.12Hz, 2H), 4.27 (t, J = 4.00 Hz, 2H), 2.71 (s, 3H), 1.83 (s, 3H) 985

MS (ESI) m/z 561.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.52 (bs,1H), 8.59 (s, 1H), 8.47 (s, 1H), 7.58 (dd, J = 8.8, 2.12 Hz, 1H), 7.41(s, 1H), 7.381H), 7.33 (d, J = 8.96 Hz, 1H), 7.28-7.20 (m, 1H), 4.36 (t,J = 5.68 Hz, 2H), 4.18 (t, J = 6.16 Hz, 2H), 2.97 (d, J = 4.24 Hz, 3H),2.69 (s, 3H), 1.75 (s, 3H) 986

MS (ESI) m/z 637.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.59 (bs,1H), 8.76 (s, 1H), 8.52 (s, 1H), 7.58 (dd, J = 8.84, 2.48 Hz, 1H),7.43-7.32 (m, 5H), 7.18 (d, J = 8.00 Hz, 2H), 7.12 (t, J = 7.20 Hz, 1H),4.35 (t, J = 5.48 Hz, 2H), 4.18 (t, J = 3.64 Hz, 2H), 3.53 (s, 3H), 2.72(s, 3H), 1.78 (s, 3H) 987

MS (ESI) m/z 651.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.45 (bs,1H), 8.69 (s, 1H), 8.62 (s, 1H), 8.13 (t, J = 3.36 Hz, 2H), 7.58 (dd, J= 2.52, 8.84 Hz, 1H), 7.53-7.51 (m, 3H), 7.42 (d, J = 2.52 Hz, 1H),7.39-7.36 (m, 2H), 4.41 (t, J = 4.60 Hz, 2H), 4.25 (t, J = 4.4 Hz, 2H),3.31 (s, 6H), 2.56 (s, 3 H) 1.88 (s, 3H) 988

MS (ESI) m/z 590.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H),8.40 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.43-7.42 (m, 2H), 7.35(d, J = 8.9 Hz, 1H), 4.95-4.90 (m, 1H), 4.39 (s, 2H), 4.23-4.20 (m, 2H),3.22 (s, 3H), 2.70 (s, 3H), 1.84 (s, 3H), 1.50 (s, 3H) 989

MS (ESI) m/z 626.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 with D2O) 6 9.14(s, 1H), 7.79 (s, 1H), 7.50 (dd, J = 8.64 Hz, 1.96 Hz, 1H), 7.31 (d, J =2.56 Hz, 1H), 7.25 (d, J = 8.68 Hz, 1H), 7.04 (s, 1H), 6.63 (s, 1H),6.41 (s, 1H), 4.33 (s, 2H), 4.25 (s, 2H), 2.66 (s, 3H), 1.82 (s, 3H) 993

MS (ESI) m/z 665.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.53 (bs,1H), 9.56 (s, 1H), 9.11 (s, 1H), 8.72 (s, 1H), 8.32 (bs, 1H), 8.28 (d, J= 8.56 Hz, 1H), 8.06 (d, J = 8.48 Hz,1H), 7.59 (dd, J = 8.92Hz, 2.36 Hz,1H), 7.41 (d, J = 2.28 Hz, 1H), 7.37-7.35 (m, 2H), 4.42 (t, J = 6.24 Hz,2H), 4.30 (t, J = 4.56 Hz, 2H), 2.70 (s, 3H), 1.90 (s, 3H) 994

MS (ESI) m/z 640.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H),8.39 (s, 1H), 7.59 (dd, J = 8.88, 2.62 Hz, 1H), 7.41 (t, J = 2.8 Hz,2H), 7.36 (d, J = 8.8 Hz, 1H), 4.40 (t, J 5.2 Hz, 2H), 4.27 (t, J = 5.2Hz, 2H), 2.94 (d, 4.4 Hz, 1H), 2.70 (s, 3H), 2.66- 2.60 (m, 1H), 1.91(s, 3H), 1.68 (t, J = 7.2 Hz, 2H) 997

MS (ESI) m/z 673.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H),8.50 (s, 1H), 7.86 (dd, J = 2.56, 6.08 Hz, 1H), 7.70 (dd, J = 4.60, 8.60Hz, 1H), 7.58 (dd, J = 2.52, 8.92 Hz, 1H), 7.49 (t, J = 9.28 Hz, 2H),7.42-7.36 (m, 2H), 4.44 (t, J = 4.40 Hz, 2H), 4.29 (t, J = 4.40 Hz, 2H),2.79 (s, 3H), 2.70 (s, 3H), 2.00 (s, 3H) 998

MS (ESI) m/z 658.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H),8.52 (s, 1H), 7.64-7.61 (m, 1H), 7.60 (dd, J = 2.4, 8.92 Hz, 1H),7.50-7.47 (m, 2H), 7.42 (bs, 1H), 7.40 (d, J = 2.56 Hz, 1H), 7.37 (d, J= 9.00 Hz, 1H), 4.44 (t, J = 4.72 Hz, 2H), 4.29 (t, J = 4.52 Hz, 2H)2.79 (s, 3H), 2.70 (s, 3H), 2.06 (s, 3H) 999

MS (ESI) m/z 674.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (bs, 1H),8.50 (s, 1H), 7.72-7.68 (m, 2H), 7.59 (dd, J = 2.56, 8.92 Hz, 1H),7.53-7.45 (m, 1H), 7.43-7.41 (m, 2H), 7.34 (d, J = 9.2 Hz, 1H), 4.45 (t,J = 4.96 Hz, 2H), 4.29 (bs, 2H), 2.78 (s, 3H), 2.70 (s, 3H), 1.98 (s,3H) 1004

MS (ESI) m/z 548.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.62 (bs,2H), 8.51 (s, 1H), 8.30 (bs, 1H), 7.59 (dd, J = 8.88, 2.52 Hz, 1H), 7.42(s, 2H), 7.34 (d, J = 9.00 Hz 1H), 4.35 (t, J = 5.48 Hz, 2H), 4.15 (t, J= 3.64 Hz, 2H), 2.71 (s, 3H), 1.65 (s, 3H) 1008

MS (ESI) m/z 663.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H),8.10-8.08 (m, 2H), 7.60 (dd, J = 2.4, 6.8 Hz, 2H), 7.51-7.50 (m, 3H),7.41-7.36 (m, 3H), 4.42 (t, J = 4.8 Hz, 6H), 4.24 (t, J = 4.4 Hz, 2H),2.57 (s, 3H), 2.42- 2.32 (m, 2H), 1.97 (s, 3H) 1010

MS (ESI) m/z 617.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H),8.55 (s, 1H), 8.47 (s, 1H), 7.58 (d, J = 8.72 Hz ,1H), 7.40- 7.38 (m,2H), 7.34 (d, J = 8.76 Hz, 1H), 4.55 (t, J = 6.76 Hz, 2H), 4.36 (m, 3H),4.18-4.13 (m, 4H), 3.28 (s, 3H), 2.70 (s, 3H), 1.80 (s, 3H) 1011

MS (ESI) m/z 603.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H),8.48 (s, 1H), 7.59 (dd, J = 2.4, 8.8 Hz 1H), 7.41 (d, J = 2.4 Hz, 1H),7.39 (s, 1H ), 7.35 (d, J = 9.2 Hz 1H), 5.79 (d, J = 5.2 Hz, 1H), 4.58(m, 3H), 4.36 (bs, 2H), 4.19 (bs, 2H), 4.07 (d, J = 6.8 Hz, 2H), 2.70(s, 3H), 1.78 (s, 3H) 1015

MS (ESI) m/z 636.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.67 (bs,1H), 8.50 (s, 1H), 7.87 (m, 2H), 7.61-7.55 (m, 4H), 7.46 (s, 1H), 7.42(d, J = 2.5 Hz, 1H), 7.37 (s, 1H), 4.45 (t, J = 5.3 Hz, 2H), 4.27 (t, J= 4.6 Hz, 2H), 3.04- 2.98 (m, 2H), 2.78 (s, 3H), 1.35 (s, 3H), 1.08 (t,J = 7.5 Hz, 3H) 1016

MS (ESI) m/z 622.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.73 (bs,1H), 9.02 (s, 1H), 8.39 (s, 1H) 7.94-7.87 (m, 2H), 7.61-7.58 (m, 4H),7.46-7.43 (m, 2H), 7.36 (d, J = 8.96 Hz, 1H), 4.42 (t, J = 5.6 Hz, 2H),4.27 (t, J = 4.32 Hz, 2H), 3.02 (q, J = 7.52 Hz, 2H), 1.83 (s, 3H) 1.35(t, J = 7.56 Hz, 3H) 1037

MS (ESI) m/z 688.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.86 (bs,1H), 8.87 (s, 1H), 8.11 (s, 1H), 7.54 (d, J = 8.72 Hz, 1H), 7.36 (s,1H), 7.30 (d, J = 8.88 Hz, 1H), 7.23 (s, 1H), 4.48 (t, J = 4.4 Hz, 1H),4.35 (t, J = 4.08, 2H), 4.22 (t, J = 3.24, 2H), 2.66 (s, 3H), 1.80 (s,3H), 0.86 (d, J = 5.56 Hz, 2H), 0.81 (s, 2H) 1038

MS (ESI) m/z 624.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (bs,1H), 8.62 (s, 1H), 8.44 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz 1H),7.54-7.46 (m, 2H), 7.45-7.40 (m, 2H), 7.36 (d, J = 8.8 Hz, 1H),7.35-7.28 m, 3H), 4.41 (t, J = 4.4 Hz, 2H), 4.26 (t, J = 5.2 Hz, 2H),2.71 (s, 3H), 1.82 (s, 3H) 1039

MS (ESI) m/z 639.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.62 (bs,1H), 8.71 (s, 1H), 8.59 (d, J = 4 Hz, 1H), 8.43 (s, 1H), 7.89 (t, J =7.08 Hz, 1H), 7.60-7.57 (m, 2H), 7.40 (s, 2H), 7.39-7.34 (m, 2H), 5.68(s, 2H), 4.40 (t, J = 5.36 Hz, 2H), 4.24 (t, J = 4.36 Hz,2H), 2.70 (s,3H), 1.85 (s, 3H) 1041

MS (ESI) m/z 653.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) ) 68.58 (s, 1H),8.46 (s, 1H), 7.58 (dd, J = 2.4, 8.8 Hz, 1H), 7.40 (t, J = 2.4 Hz, 2H),7.35 (d, J = 8.8 Hz, 1H), 7.03-6.65 (m, 1H), 5.12 (t, J = 3.6 Hz, 1H),4.72 (m, 2H), 4.38 (t, J = 5.2 Hz, 2H), 4.32 (m, 2H), 4.21 (t, J = 4.4Hz, 2H), 3.40 (s, 1H), 2.71 (s, 3H), 1.83 (s, 3H) 1042

MS (ESI) m/z 671.16 [M + 1]-; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H),8.47 (s, 1H), 7.60 (dd, J = 2.8, 8.8 Hz, 1H), 7.41-7.40 (m, 2H), 7.36(d, J = 8.8 Hz, 1H), 5.36-5.33 (m, 1H), 4.79-4.75 (m, 2H), 4.43 (t, J =3.2 Hz, 2H), 4.40 (t, J = 7.6 Hz, 2H), 4.21 (d, J = 4.4 Hz, 2H), 2.17(s, 3H), 1.85 (s, 3H) 1043

MS (ESI) m/z 667.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H),8.47 (s, 1H), 7.57 (dd, J = 2.52, 8.8 Hz ,1H), 7.40 (t, J = 2.4 Hz, 2H),7.34 (d, J = 8.84 Hz, 1H), 6.35-6.06 (m, 1H), 4.59 (t, J = 6.24 Hz, 2H),4.36 (t, J = 4.8 Hz, 2H), 4.18 (d, J = 6.8 Hz, 4H), 3.84-3.75 (m, 2H),2.70 (s, 3H), 1.80 (s, 3H) 1044

MS (ESI) m/z 685.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (bs,1H), 8.57 (s, 1H), 8.47 (s, 1H), 7.58 (dd, J = 2.48, 8.88 Hz ,1H), 7.40(d, J = 2.56 Hz, 1H), 7.39 (s, 1H), 7.34 (d, J = 9.00 Hz, 1H), 4.65-4.58(m, 3H), 4.37 (t, J = 6.08 Hz, 2H), 4.25-4.19 (m, 6H), 2.70 (s, 3H),1.81 (s, 3H) 1045

MS (ESI) m/z 659.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.59 (bs,1H), 8.55 (s, 1H), 8.47 (s, 1H), 7.59 (dd, J = 2.48, 8.84 Hz, 1H), 7.41(d, J = 2.52 Hz, 1H), 7.39 (s, 1H), 7.34 (d, J = 8.96 Hz, 1H), 4.68-4.65(m, 1H), 4.61-4.57 (m, 2H), 4.34 (t, J = 4.68 Hz, 2H), 4.16 (t, J = 3.72Hz, 2H), 4.06-4.03 (m, 2H), 2.67 (s, 3H), 1.82 (s, 3H), 1.15 (s, 9H)1051

MS (ESI) m/z 641.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.52 (s, 1H),9.06 (s, 1H), 8.67 (d, J = 2.76 Hz, 1H), 8.36 (s, 1H), 8.06 (dd, J =2.64, 9.0 Hz, 1H), 7.60 (dd, J = 2.52, 8.8 Hz ,1H), 7.43 (s, 2H), 7.36(d, J = 8.96 Hz, 1H), 4.43 (t, J = 5.0 Hz, 2H), 4.29 (t, J = 5.5 Hz,2H), 2.72 (s, 3H), 2.36 (s, 3H), 1.91 (s, 3H) 1052

MS (ESI) m/z, 640.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.51 (bs,1H), 9.03 (s, 1H), 8.37 (s, 1H), 7.60 (dd, J = 2.40, 8.84 Hz, 1H), 7.43(bs, 4H), 7.34 (d, J = 8.92 Hz, 1H), 7.32- 7.28 (m, 1H), 4.42 (t, J =4.72 Hz, 2H), 4.27 (t, J = 4.76 Hz, 2H), 2.72 (s, 3H), 2.14 (s, 3H),1.86 (s, 3H) 1053

MS (ESI) m/z 603.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H),8.38 (s, 1H), 7.59 (d, J = 8.72 Hz, 1H), 7.42 (s, J = 2.76, 2H), 7.36(d, J = 8.96 Hz, 1H), 4.41 (s, 2H), 4.26 (s, 2H), 3.34 (s, 3H), 2.71 (s,3H), 2.00 (bs, 3H), 1.84 (s, 3H) 1056

MS (ESI) m/z 617.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H),8.50 (s, 1H), 7.59 (dd, J = 8.8 Hz, 2.44 Hz, 1H), 7.42-7.40 (m, 2H),7.35 (d, J = 9 Hz, 1H), 4.38 (bs, 1H), 4.36 (m, 2H), 4.21-4.18 (m, 2H),3.93-3.87 (m, 3H), 3.78-3.73 (m,1H), 3.56 (d, J = 11.68 Hz, 1H), 2.70(s, 3H), 2.04-2.02 (m, 1H), 1.94-1.92 (m, 1H), 1.79 (s, 3H) 1057

MS (ESI) m/z 617.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.59 (bs,1H), 8.56 (s, 1H), 8.47 (s, 1H), 7.58 (d, J = 8.64 Hz, 1H), 7.40 (d, J =8.84 Hz, 2H), 7.34 (d, J = 8.88 Hz, 1H), 5.70 (bs, 1H) 4.36 (t, J = 6.56Hz, 2H), 4.20 (m, 6H), 2.70 (s, 3H), 1.77 (s, 3H), 1.47 (s, 3H) 1062

MS (ESI) m/z 574.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.7 (bs, 1H),8.92 (s, 1H), 8.35 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.44-7.43 (m, 2H),7.36 (d, J = 8.8 Hz, 1H), 4.40 (t, J = 4.4 Hz, 2H), 4.25 (t, J = 4.0 Hz,2H), 3.12- 3.07(m, 2H), 3.03-2.97 (m, 2H), 1.83 (s, 3H), 1.36 (t, J =7.2 Hz, 6H) 1063

MS (ESI) m/z 573.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H),8.30 (s, 1H), 7.55 (dd, J = 8.88 Hz, 2.32 Hz, 1H), 7.35-7.30 (m, 3H),4.36 (t, J = 6.6 Hz, 2H), 4.22 (t, J = 5.12 Hz, 2H), 3.02 (t, J = 7.36Hz, 2H), 2.71 (s, 3H), 1.90 (s, 3H), 1.80-1.74 (m, 2H),0.93 (t, J =14.6Hz, 3H) 1064

MS (ESI) m/z 578.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H),8.40 (s, 1H), 7.59 (dd, J = 8.88 Hz, 2.62 Hz, 1H), 7.41 (s, 2H), 7.35(d, J = 8.89 Hz, 1H), 4.94 (dt, J = 48 Hz, 6.0 Hz, 2H), 4.40 (t, J = 5.2Hz, 2H), 4.26 (t, J = 4.8 Hz, 2H), 3.49 (dt, J = 25 Hz, 6.0 Hz, 2H),2.70 (s, 3H), 1.89 (s, 3H) 1065

MS (ESI) m/z 578.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (bs,1H), 9.03 (s, 1H), 8.39 (s, 1H), 7.59 (dd, J = 8.8, 2.2 Hz 1H),7.45-7.38 (m, 2H), 7.35 (d, J = 8.92 Hz, 1H), 6.24-6.15 (dq, J = 47.20,6.80 Hz, 1H), 4.47- 4.35 (m, 2H), 4.35-4.29 (m, 2H), 2.69 (s, 3H), 1.87(s, 3H), 1.78 (dd, J = 24.4, 6.32 Hz, 3H) 1066

MS (ESI) m/z 576.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H),8.98 (s, 1H), 8.35 (s, 1H), 7.58 (s, 1H), 7.41-7.35 (m, 3H), 4.74 (s,2H), 4.39 (s, 2H), 4.26 (s, 2H), 3.38 (s, 3H) 2.69 (s, 3H), 1.85 (s, 3H)1067

MS (ESI) m/z 576.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H),8.42 (s, 1H), 7.57 (dd, J = 2.52, 8.8 Hz, 1H), 7.41 (s, 2H), 7.35 (d, J= 8.92 Hz, 1H), 4.59-4.54 (m, 2H), 4.39 (t, J = 4.4 Hz, 2H), 4.23 (t, J= 4.3 Hz, 2H), 2.71 (s, 3H), 1.84 (s, 3H) 1068

MS (ESI) m/z 602.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.70 (bs,1H), 8.69 (s, 1H), 8.37 (s, 1H), 7.59 (dd, J = 8.88, 2.64 Hz, 1H), 7.40(d, J = 2.60 Hz, 1H), 7.38 (s, 1H), 7.34 (d, J = 8.96 Hz, 1H), 4.41-4.31(m, 4H), 4.23 (t, J = 4.60 Hz, 2H), 2.70 (s, 3H), 1.83 (s, 3H), 1.40-1.40 (m, 1H), 0.65-0.58 (m, 2H), 0.46-0.39 (m, 2H) 1068

MS (ESI) m/z 561.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.59 (bs,1H), 8.55 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.40-7.34 (m, 3H), 7.03 (s,2H), 4.38 (t, J = 5.9 Hz, 2H), 4.17 (t, J = 4.0 Hz, 2H), 2.69 (s, 3H),2.56 (s, 3H), 1.72 (s, 3H) 1070

MS (ESI) m/z 575.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H),7.60 (dd, J = 2.0, 8.8 Hz, 1H), 7.44 (t, J = 3.6 Hz, 2H), 7.36 (d, J =9.2 Hz, 1H), 7.03 (bs, 2H), 4.40 (bs, 2H), 4.17 (bs, 2H), 3.03 (m, 2H),2.55 (s, 3H), 1.69 (s, 3H), 2.96 (t, J = 7.6 Hz, 3H) 1071

MS (ESI) m/z 561.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.80 (bs,1H), 8.47 (s, 1H), 8.44 (s, 1H) 7.59 (d, J = 9.20 Hz, 1H), 7.44 (s, 2H),7.33 (d, J = 9.0 Hz, 1H), 7.21 (bs, 2H), 4.35 (t, J = 5.48 Hz, 2H), 4.16(t, J = 6.28 Hz, 2H), 3.01 (q, J = 7.52 Hz, 2H), 1.64 (s, 3H), 1.34 (t,J = 7.48 Hz, 3H) 1072

MS (ESI) m/z 547.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H),8.47 (s, 1H) 7.59 (dd, J = 8.92, 2.44 Hz, 1H), 7.45-7.39 (m, 2H), 7.33(d, J = 8.92 Hz 1H), 7.21 (bs, 2H), 4.36 (t, J = 6.0 Hz, 2H), 4.17 (t, J= 6.04 Hz, 2H), 2.70 (s, 3H), 1.68 (s, 3H) 1076

MS (ESI) m/z 600.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.71 (s, 1H),8.81 (s, 1H), 8.35 (s, 1H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H), 7.43 (s,1H), 7.36 (d, J = 9.2 Hz, 1H), 4.41 (t, J = 4.8 Hz, 2H), 4.24 (t, J =4.4 Hz, 2H), 2.96 (t, J = 7.2 Hz, 2H), 2.66 (m, 1H), 1.85-1.75 (m, 5H),1.23-1.18 (m, 2H), 1.10-1.06 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H) 1086

MS (ESI) m/z 644.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.70 (bs,1H), 9.90 (bs, 1H), 8.66 (s, 1H), 8.38 (s, 1H) 7.60 (dd, J = 8.88, 2.36Hz, 1H), 7.46 (s, 1H), 7.41 (d, J = 2.36 Hz 1H), 7.37 (d, J = 8.96 Hz,1H), 4.40 (t, J = 4.88 Hz, 2H), 4.31 (d, J = 13.92 Hz, 2H), 4.22 (t, J =5.84 Hz, 2H), 3.61 (d, J = 11.36 Hz, 2H), 3.44 (t, J = 11.92 Hz, 2H),3.30-3.28 (m, 2H), 3.02 (q, J = 7.44 Hz, 2H), 2.91 (s, 3H), 1.84 (s,3H), 1.37 (t, J = 7.52 Hz, 3H) 1089

MS (ESI) m/z 586.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 8.75 (s, 1H),7.68 (s, 1H), 7.52 (d, J = 7.0 Hz, 1H), 7.34-7.28 (m, 3H), 7.09 (s, 1H),4.34(5, 2H), 4.20 (s, 2H), 3.65 (s, 4H), 2.58 (s, 4H), 2.49 (s, 3H),2.24 (s, 3H), 1.8 (s, 3H) 1091

MS (ESI) m/z 644.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.39 (bs,1H), 8.62 (s, 1H), 7.59 (dd, J = 2.48, 8.88 Hz ,1H), 7.40-7.38 (m, 2H),7.35 (d, J = 8.92 Hz, 1H), 4.63-4.59 (m, 2H), 4.47 (bs, 2H), 4.39 (t, J= 4.64 Hz, 2H), 4.23 (t, J = 4.64 Hz, 3H), 2.82 (bs, 6H), 2.70 (s, 3H),2.54 (s, 3H), 1.94 (s, 3H) 1092

MS (ESI) m/z 670.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H),7.55 (d, J = 8.8 Hz, 1H), 7.33-7.30 (m, 3H), 4.88 (s, 2H), 4.35 (s, 2H),4.22 (s, 2H), 3.53 (d, J = 12 Hz, 2H), 3.31 (d, J = 11.6 Hz, 2H), 2.79(s, 3H), 2.66 (s, 3H), 2.46 (s, 3H), 2.05 (s, 7H) 1097

MS (ESI) m/z 651.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H),8.42 (s, 1H), 7.59 (dd, J = 8.8, 2.56 Hz, 1H), 7.41 (s, 2H), 7.36 (d, J= 8.95 Hz, 1H), 4.39 (t, J = 6.9 Hz, 2H), 4.22 (t, J = 4.56 Hz, 2H),3.87-3.75 (m, 4H), 2.71 (s, 3H), 2.21-2.15 (m, 4H) 1.87 (s, 3H) 1099

MS (ESI) m/z 325.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.28 (m,5H), 7.19 (d, J = 7.9 Hz, 1H), 4.99 (s, 2H), 3.50 (t, J = 12.4 Hz, 4H),3.29-3.17 (m, 1H), 2.04 (t, J = 10.8 Hz, 2H), 1.77 (d, J = 12.4 Hz, 2H),1.70 (d, J = 12.8 Hz, 2H), 1.15 (dq, J = 12.9, 3.2 Hz, 2H), 0.99 (q, J =13.3 Hz, 2H) 1100

MS (ESI) m/z 714.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.7 Hz, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 7.78-7.74 (m, 1H), 7.69 (dd, J= 6.4, 2.2 Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.92 (br, 4H), 4.82 (s,2H), 4.33 (br, 2H), 3.13 (s, 3H), 2.07 (s, 3H), 2.03-1.61 (m, 8H) 1101

MS (ESI) m/z 670.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.77 (s, 1H), 8.36 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 4.40 (br, 2H), 4.23 (br, 2H), 3.81-3.03 (br, 6H), 1.79 (s, 3H),1.62 (br, 3H), 1.31 (br, 4H), 0.96-0.75 (m, 4H) 1102

MS (ESI) m/z 664.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.63 (s, 1H), 7.78-7.73 (m, 1H), 7.69 (dd, J =6.6, 2.2 Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.85 (d, J = 7.1 Hz, 2H),3.83-2.97 (br, 6H), 2.12 (s, 3H), 1.63 (br 3H), 1.34 (br, 3H), 1.23-0.78(m, 5H) 1103

MS (ESI) m/z 738.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 7.78-7.73 (m, 1H), 7.71-7.67(m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 6.79-6.41 (m, 1H), 4.82 (s, 2H), 4.36(br, 1H), 3.11 (s, 3H), 2.07 (s, 3H), 2.05-1.82 (br, 2H). Protons onpiperidine were not seen 1104

MS (ESI) m/z 722.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H),8.74 (d, J = 4.7 Hz, 1H), 8.62 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H),7.71-7.61 (m, 2H), 7.43 (d, J = 4.7 Hz, 1H), 4.82 (s, 2H), 4.54 (bs,2H), 3.86 (s, 3H), 3.68- 3.23 (br, 2H), 2.15 (s, 3H). Some aliphaticprotons were not seen 1105

MS (ESI) m/z 829.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.9 Hz, 1H), 8.82 (s, 1H), 8.75 (s, 1H), 7.78 (d, J = 9.1 Hz, 1H), 7.71(dd, J = 6.6, 2.2 Hz, 2H), 7.64 (d, J = 4.9 Hz, 1H), 7.26-6.94 (m, 1H),6.59 (tt, J = 54.1, 4.3 Hz, 2H), 4.84 (s, 2H), 4.56 (br, 1H), 4.48 (td,J = 14.7, 4.3 Hz, 2H), 3.12 (s, 3H), 2.34-1.97 (br, 8H), 1.95 (s, 3H),1.76 (t, J = 19.4 Hz, 3H) 1106

MS (ESI) m/z 710.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 7.76 (d, J = 9.0Hz, 1H), 7.71-7.66 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 5.00-4.86 (m, 1H),4.83 (s, 2H), 4.81-4.68 (m, 1H), 3.78-3.29 (m, 2H), 3.19 (s, 3H), 2.87(s, 3H), 2.44-2.11 (m, 5H), 2.08 (s, 3H), 2.06-1.77 (m, 5H) 1107

MS (ESI) m/z 752.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 7.78-7.74 (m, 1H), 7.71-7.67(m, 2H), 7.55 (d, J = 4.9 Hz, 1H), 4.82 (s, 2H), 4.38 (br, 1H), 3.11 (s,3H), 2.08 (s, 3H), 2.07-1.92 (br, 2H), 1.84 (t, J = 20.0 Hz, 3H).Piperidine protons were not seen 1108

MS (ESI) m/z 791.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H),8.82-8.78 (m, 2H), 8.76 (s, 1H), 7.77 (dd, J = 8.3, 0.6 Hz, 1H),7.73-7.66 (m, 2H), 7.62 (d, J = 4.9 Hz, 1H), 4.83 (s, 2H), 4.78 (br,4H), 4.36-4.22 (m, 2H), 3.54 (s, 3H), 3.09 (s, 3H), 2.12-2.02 (m, 2H),1.98 (s, 3H), 1.80-1.67 (m, 3H), 1.46-1.32 (m, 3H) 1109

MS (ESI) m/z 854.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H),8.89 (d, J = 4.8 Hz, 1H), 8.72 (ddd, J = 4.6, 1.7, 0.9 Hz, 1H), 8.66 (s,1H), 8.59 (s, 1H), 8.27 (dt, J = 8.0, 1.1 Hz, 1H), 8.25-8.18 (m, 1H),7.79-7.72 (m, 2H), 7.72-7.68 (m, 2H), 7.66 (d, J = 4.9 Hz, 1H), 4.82 (s,2H), 4.76 (br, 4H), 4.34-4.23 (m, 1H), 3.24 (br, 1H), 3.07 (s, 3H),2.13-2.01 (m, 2H), 1.97 (br, 2H), 1.94 (s, 3H), 1.71 (q, J = 12.1 Hz,2H), 1.38 (q, J = 12.0 Hz, 2H) 1110

MS (ESI) m/z 854.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.29 (dd, J =2.4, 0.8 Hz, 1H), 8.92 (dd, J = 4.8, 1.6 Hz, 1H), 8.83 (d, J = 4.9 Hz,1H), 8.69 (s, 1H), 8.54 (ddd, J = 8.2, 2.4, 1.6 Hz, 1H), 8.47 (s, 1H),7.77-7.67 (m, 3H), 7.66 (dd, J = 2.2, 0.5 Hz, 1H), 7.62 (dd, J = 4.8,0.4 Hz, 1H), 4.84 (br, 4H), 4.80 (s, 2H), 4.39-4.27 (m, 1H), 3.28 (br,1H), 3.09 (s, 3H), 2.14-2.05 (m, 2H), 2.02-1.94 (m, 2H), 1.91 (s, 3H),1.74 (q, J = 12.2 Hz, 2H), 1.42 (q, J = 11.9 Hz, 2H) 1111

MS (ESI) m/z 854.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.98-8.93 (m,2H), 8.84 (d, J = 4.9 Hz, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 8.11- 7.70(dd, J = 8.4, 2.2 Hz, 1H), 7.66 (dd, J = 2.2, 0.5 Hz, 1H), 7.64 (dd, J =4.9, 0.4 Hz, 1H), 4.84 (br, 4H), 4.81 (s, 2H), 4.38-4.25 (m, 1H), 3.28(br, 1H), 3.08 (s, 3H), 2.15-2.06 (m, 2H), 2.01-1.94 (m, 2H), 1.92 (s,3H), 1.73 (q, J = 12.1 Hz, 2H), 1.41 (q, J = 11.8 Hz, 2H) 1112

MS (ESI) m/z 688.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 7.77-7.74 (m, 1H), 7.71-7.67(m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 6.52 (t, J = 53.4 Hz, 1H), 4.83 (s,2H), 4.50 (bs, 1H), 3.11 (s, 3H), 2.25-1.98 (m, 7H) 1113

MS (ESI) m/z 702.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.7 Hz, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 7.74 (dd, J = 8.1, 0.8 Hz, 1H),7.68-7.64 (m, 2H), 7.44 (d, J = 4.7 Hz, 1H), 6.15 (tt, J = 55.8, 4.4 Hz,1H), 4.81 (s, 2H), 4.26 (ddt, J = 11.6, 7.7, 4.0 Hz, 1H), 3.84 (s, 3H),3.10 (s, 3H), 3.03 (d, J = 11.2 Hz, 2H), 2.76 (td, J = 15.7, 4.3 Hz,2H), 2.33 (t, J = 11.5 Hz, 2H), 2.03 (s, 3H), 1.92 (qd, J = 12.1, 3.9Hz, 2H), 1.79 (d, J = 11.7 Hz, 2H); 19F NMR (377 MHz, DMSO-d6) 6-118.73(dt, J = 55.8, 15.7 Hz, 2F) 1115

MS (ESI) m/z 683.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H),8.79 (d, J = 4.8 Hz, 1H), 8.59 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.35 (d, J = 9.0 Hz,1H), 4.42 (t, J = 4.9 Hz, 2H), 4.25 (t, J = 5.0 Hz, 2H), 3.82- 3.70 (m,1H), 3.20-3.09 (m, 2H), 2.78-2.67 (m, 2H), 1.92-1.79 (m, 7H) 1116

MS (ESI) m/z 677.1 [M + 1]+; 1H NMR (400 MHz, Chloroform-d) δ 9.16 (s,1H), 8.78 (d, J = 4.9 Hz, 1H), 8.56 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H),7.51 (dd, J = 8.4, 2.1 Hz, 1H), 7.46-7.41 (m, 2H), 4.81 (s, 2H),3.66-3.38 (m, 5H), 3.01 I (t, J = 11.8 Hz, 2H), 2.50-2.31 (m, 5H), 2.13(d, J = 14.0 Hz, 2H) 1117

MS (ESI) m/z 683.3 [M + 1]+; 1H NMR (400 MHz, Chloroform-d) δ 9.12 (s,1H), 8.78 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 7.48 (dd, J = 8.9, 2.6 Hz,1H), 7.32-7.27 (m, 2H), 7.03 (d, J = 8.9 Hz, 1H), 4.41 (t, J = 4.9 Hz,2H), 4.29 (t, J = 4.9 Hz, 2H), 3.64-3.48 (m, 6H), 3.13-3.01 (m, 2H),2.46-2.32 (m, 2H), 1.89 (s, 3H) 1118

MS (ESI) m/z 694.3 [M + 1]+; 1H NMR (400 MHz, Chloroform-d) δ 8.75 (s,1H), 8.71 (d, J = 4.8 Hz, 1H), 8.49 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H),7.52 (dd, J = 8.4, 2.1 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.38 (d, J =4.9 Hz, 1H), 5.36 (d, J = 7.0 Hz, 2H), 4.77-4.64 (m, 3H), 4.34 (d, J =7.0 Hz, 2H), 3.37 (d, J = 11.5 Hz, 2H), 3.28 (t, J = 12.1 Hz, 2H), 3.19(s, 3H), 2.84-2.70 (m, 2H), 2.44 (s, 3H), 2.34 (d, J = 13.5 Hz, 2H),1.85 (s, 3H) 1119

MS (ESI) m/z 756.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 7.76 (d, J = 9.0 Hz, 1H),7.71-7.66 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.35-4.24 (m,1H), 3.38- 3.22 (m, 2H), 3.12-3.00 (m, 5H), 2.63-2.52 (m, 2H), 2.06 (s,3H), 2.00-1.86 (m, 2H), 1.85- 1.75 (m, 2H) 1120

MS (ESI) m/z 623.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80-8.58 (m,3H), 7.78- 7.63 (m, 3H), 7.53 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.27(t, J = 11.8 Hz, 1H), 3.09 (s, 3H), 2.04 (s, 3H), 1.89-1.75 (m, 4H),1.71-1.56 (m, 3H), 1.38 (q, J = 12.8, 12.2 Hz, 2H), 1.16 (q, J = 13.1Hz, 1H) 1121

LCMS (ESI) m/z 677.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.36 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.44 (s, 1H), 7.42 4.41 (t, J = 4.9 Hz, 2H),4.33-4.09 (m, 4H), 2.08 (d, J = 4.4 Hz, 3H), 1.80 (s, 3H) 1122

LCMS (ESI) m/z 631.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.37 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz,2H), 7.05 (dt, J = 14.5, 6.8 Hz, 1H), 5.46 (d, J = 57.5 Hz, 1H), 4.56(s, 2H), 4.46-4.32 (m, 4H), 4.26 (t, J = 5.0 Hz, 4H), 1.79 (s, 3H) 1123

LCMS (ESI) m/z 627.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.38 (s, 1H), 7.67-7.58 (m, 2H), 7.48 (d, J =4.8 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H), 7.04(d, J = 15.0 Hz, 1H), 4.42 (t, J = 5.0 Hz, 2H), 4.28 (t, J = 5.0 Hz,2H), 2.98 (s, 6H), 1.86 (s, 3H), 1.53 (s, 2H), 1.35 (s, 2H) 1124

LCMS (ESI) m/z 677.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H),8.84 (dd, J = 4.8, 1.4 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 7.60 (ddd, J =9.0, 2.7, 0.8 Hz, 1H), 7.50 (s, 1H), 7.51-7.41 (m, 1H), 7.35 (d, J = 9.0Hz, 1H), 7.11 (d, J = 15.4 Hz, 1H), 6.93 (d, J = 15.4 Hz, 1H), 6.06 (tt,J = 56.0, 4.2 Hz, 1H), 4.40 (t, J = 4.9 Hz, 2H), 4.24 (t, J = 4.9 Hz,2H), 3.19 (td, J = 15.5, 4.2 Hz, 2H), 2.61 (s, 3H), 1.73 (d, J = 1.3 Hz,3H), 1.16-1.13 (m, 2H), 1.12-1.01 (m, 2H) 1125

LCMS (ESI) m/z 728.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78-8.71 (m,2H), 8.64 (s, 1H), 7.75 (dd, J = 7.9, 1.0 Hz, 1H), 7.71-7.64 (m, 2H),7.54 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 2.09 (s, 3H), 0.70 (s, 2H), 0.65(s, 2H) 1126

LCMS (ESI) m/z 734.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =4.8 Hz, 1H), 8.58 (s, 1H), 8.38 (s, 1H), 7.57 (dd, J = 8.9, 2.7 Hz, 1H),7.47-7.37 (m, 2H), 7.33 (d, J = 9.0 Hz, 1H), 4.49 (bs, 1H), 4.36 (t, J =4.9 Hz, 2H), 4.18 (t, J = 4.9 Hz, 2H), 2.99 (s, 3 H), 1.73 (s, 3H), 1.51(ddd, J = 13.2, 8.1, 4.9 Hz, 1H), 0.71- 0.60 (m, 4H) 1127

LCMS (ESI) m/z 714.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =4.8 Hz, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 7.57 (dd, J = 8.9, 2.7 Hz, 1H),7.44 (d, J = 4.8 Hz, 1H), 7.39-7.29 (m, 2H), 4.51 (s, 1H), 4.46-4.30 (m,4H), 4.19 (t, J = 5.1 Hz, 2H), 3.50 (d, J = 11.8 Hz, 2H), 3.26-3.11 (m,2H), 3.08 (s, 3H), 2.75-2.66 (m, 1H), 2.25 (d, J = 12.7 Hz, 2H), 2.03(d, J = 12.8 Hz, 2H), 1.79 (s, 3H), 1.07 (d, J = 6.9 Hz, 6H) 1128

LCMS (ESI) m/z 712.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =4.8 Hz, 1H), 8.53 (s, 1H), 8.33 (s, 1H), 7.57 (dd, J = 8.9, 2.7 Hz, 1H),7.44 (d, J = 4.9 Hz, 1H), 7.38-7.30 (m, 2H), 4.58-4.43 (m, 3H), 4.36 (t,J = 5.1 Hz, 2H), 4.19 (t, J = 5.0 Hz, 2H), 3.52 (d, J = 11.8 Hz, 3H),3.18 (t, J = 12.7 Hz, 2H), 3.07 (s, 3H), 2.24 (d, J = 12.7 Hz, 2H),2.17-1.95 (m, 3H), 1.80 (s, 3H), 1.06 (dd, J = 23.8, 2.3 Hz, 4H) 1129

LCMS (ESI) m/z 730.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.71 (m,2H), 8.65 (s, 1H), 7.76 (dd, J = 7.9, 1.0 Hz, 1H), 7.72-7.66 (m, 2H),7.55 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 3.11 (s, 3H), 2.40-2.18 (m, 2H),2.11 (s, 4H), 1.03 (d, J = 6.9 Hz, 6H) 1130

LCMS (ESI) m/z 469.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76-8.69 (m,4H), 8.62 (s, 2H), 7.76-7.61 (m, 7H), 7.52 (d, J = 4.8 Hz, 2H), 4.79 (s,5H), 4.51 (s, 1H), 3.71 (s, 1H), 3.34 (s, 1H), 2.07 (s, 8H), 2.01 (s,1H), 1.22 (s, 14H) 1131

LCMS (ESI) m/z 744.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.68 (d, J = 14.8 Hz, 2H), 7.76 (d, J = 9.0 Hz, 1H),7.73-7.66 (m, 2H), 7.55 (d, J = 4.7 Hz, 1H), 4.82 (s, 2H), 4.21 (d, J =6.9 Hz, 1H), 3.75 (s, 1H), 3.07 (s, 3H), 3.00 (s, 2H), 2.05 (s, 3H),1.77 (s, 4H), 0.85 (s, 4H) 1132

LCMS (ESI) m/z 718.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J =4.8 Hz, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 7.72 (d, J = 8.9 Hz, 1H),7.68-7.63 (m, 2H), 7.51 (d, J = 4.8 Hz, 1H), 4.79 (s, 2H), 4.50 (s, 1H),3.71 (t, J = 13.7 Hz, 7H), 3.08 (s, 3H), 2.22 (s, 2H), 2.06 (s, 3H),2.03-1.91 (m, 2H) 1133

LCMS (ESI) m/z 732.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79-8.71 (m,2H), 8.65 (s, 1H), 7.79-7.72 (m, 1H), 7.72-7.65 (m, 2H), 7.55 (d, J =4.8 Hz, 1H), 4.82 (s, 2H), 3.76 (s, 2H), 3.11 (s, 3H), 2.08 (s, 3H) 1134

LCMS (ESI) m/z 720.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76-8.68 (m,2H), 8.62 (s, 1H), 7.76-7.69 (m, 1H), 7.69-7.62 (m, 2H), 7.52 (d, J =4.8 Hz, 1H), 4.86-4.58 (m, 2H), 4.79 (s, 3H), 4.42 (s, 1H), 2.05 (s,3H), 1.92 (bs, 3H) 1135

LCMS (ESI) m/z 744.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =1.8 Hz, 2H), 8.65 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.9Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 6.72 (t, J = 75.2 Hz, 1H), 4.83 (s,2H), 4.78 (s, 1H), 4.56 (s, 1H), 3.94 (d, J = 8.4 Hz, 1H), 3.57 (d, J =11.9 Hz, 2H), 3.12 (s, 3H), 3.06 (d, J = 10.5 Hz, 2H), 2.77-2.64 (m,2H), 2.54 (s, 1H), 2.11 (s, 7H). 19F NMR (377 MHz, DMSO-d6) 6-73.82-82.25 (d, J = 75.1 Hz) 1136

LCMS: 1.77 Min, 700.2. [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 610.73 (s,1H), 8.78-8.72 (m, 2H), 8.64 (s, 1H), 7.81-7.73 (m, 1H), 7.72 J = 53.2Hz, 1H), 4.82 (s, 2H), 4.12 (s, 4H), 3.92 (t, J = 16.0 Hz, 2H), 3.64 (d,J = 31.4 Hz, 4H), 2.06 (s, 3H) 1137

LCMS: 1.71 Min, 714.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s,1H), 8.81-8.72 (m, 2H), 8.64 (s, 1H), 7.79-7.72 (m, 1H), 7.71 (s, 2H),4.32-3.89 (m, 6H), 3.64 (m, 4H), 2.07 (d, J = 1.6 Hz, 6H), 2.00 (s, 3H),1.74 (t, J = 19.6 Hz, 3H) 1139

MS (ESI) m/z 708.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 4.39 (t, J = 5.0 Hz, 2H), 4.21 (t, J = 5.0 Hz, 2H), 3.75- 3.30 (m,10H), 3.09 (s, 3H), 1.75 (s, 6H) 1140

MS (ESI) m/z 706.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.69 (d, J = 22.6 Hz, 2H), 7.76 (d, J = 9.0 Hz, 1H),7.71-7.66 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.31 (s, 1H),3.34 (s, 1H), 3.10 (s, 5H), 2.61 (s, 2H), 2.06 (s, 3H), 1.96 (q, J =11.8 Hz, 2H), 1.82 (d, J = 12.1 Hz, 2H) 1141

MS (ESI) m/z 702.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 7.78-7.74 (m, 1H), 7.71-7.67(m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 3.11 (s, 3H), 2.09 (s,3H), 1.78 (t, J = 19.5 Hz, 3H) 1142

MS (ESI) m/z 698.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78-8.73 (m,2H), 8.65 (s, 1H), 7.76 (dd, J = 8.1, 0.8 Hz, 1H), 7.72-7.66 (m, 2H),7.55 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.57 (d, J = 12.1 Hz, 1H), 3.67(d, J = 12.6 Hz, 2H), 3.48 (dd, J = 22.6, 5.0 Hz, 2H), 3.33 (d, J = 11.5Hz, 1H), 3.12 (s, 3H), 2.40-2.26 (m, 2H), 2.15-1.98 (m, 5H), 1.50 (d, J= 21.4 Hz, 6H) 1143

MS (ESI) m/z 842.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400MHz, DMSO- d6) 613.21 (bs, 1H), 9.97 (s, 1H), 8.97-8.93 (m, 2H), 8.85(d, J = 4.9 Hz, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.10-8.05 (m, 2H), 7.77(dd, J = 8.4, 0.5 Hz, 1H), 7.70 (dd, J = 8.4, 2.2 Hz, 1H), 7.66 (dd, J =2.2, 0.5 Hz, 1H), 7.64 (dd, J = 4.9, 0.4 Hz, 1H), 4.82 (s, 2H), 4.57 (s,1H), 3.96- 3.26 (m, 4H), 3.11 (s, 3H), 2.26 (s, 2H), 2.04 (dd, J = 20.6,10.2 Hz, 2H), 1.92 (s, 3H), 1.78 (t, J = 19.5 Hz, 3H) 1144

MS (ESI) m/z 842.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H),9.28 (d, J = 2.3 Hz, 1H), 8.92 (d, J = 4.6 Hz, 1H), 8.84 (d, J = 4.9 Hz,1H), 8.67 (s, 1H), 8.56-8.51 (m, 1H), 8.48 (s, 1H), 7.73 (ddd, J = 16.1,10.9, 8.4 Hz, 3H), 7.66 (d, J = 2.2 Hz, 1H), 7.63 (d, J = 4.9 Hz, 1H),4.81 (s, 2H), 3.11 (s, 3H), 1.90 (s, 3H) 1145

MS (ESI) m/z 630.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H),8.69 (s, 1H), 8.41 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (s,1H), 7.40 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.40 (t, J =5.1 Hz, 2H), 4.31 (d, J = 14.2 Hz, 2H), 4.24 (t, J = 5.1 Hz, 2H), 3.61(d, J = 12.0 Hz, 2H), 3.45 (t, J = 13.1 Hz, 2H), 3.24 (q, J = 10.2 Hz,2H), 2.91 (d, J = 3.4 Hz, 3H), 2.72 (s, 3H), 1.90 (s, 3H) 1146

MS (ESI) m/z 842.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400MHz, DMSO- d6) δ 13.03 (s, 1H), 8.90 (d, J = 4.9 Hz, 1H), 8.72 (ddd, J =4.6, 1.7, 0.9 Hz, 1H), 8.65 (s, 1H), 8.60 (s, 1H), 8.30-8.25 (m, 1H),8.21 (td, J = 7.7, 1.7 Hz, 1H), 7.80-7.72 (m, 2H), 7.72- 7.68 (m, 2H),7.66 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 3.09 (s, 3H), 1.94 (s, 3H), 1.77(t, J = 18.9 Hz, 2H) 1148

MS (ESI) m/z 676.21. [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.22 (bs,1H), 8.83 (d, J = 4.6 Hz, 1H), 8.49 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H),7.87 (t, J = 7.4 Hz, 1H), 7.77 (m, 2H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H),7.47 (d, J = 4.7 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.9 Hz,1H), 4.44 (s, 2H), 4.27 (s, 2H), 2.77 (s, 3H), 1.85 (s, 3H) 1149

MS (ESI) m/z 631.26 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.60 (bs,1H), 8.56 (s, 1H), 7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.40-7.35 (m, 3H),5.02 (bs, 1H), 4.39 (s, 2H), 4.19 (s, 2H), 3.90-3.82 (m, 2H), 3.74 (t, J= 8.0 Hz, 1H), 3.54 (d, J = 11.6 Hz 1H), 2.70 (s, 3H), 2.59 (s, 3H),2.05-1.85 (m, 2H), 1.84 (s, 3H) 1152

MS (ESI) m/z 616.24 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.56 (bs,1H), 9.01 (s, 1H), 8.39 (s, 1H), 7.59 (dd, J = 2.8, 9.2 Hz, 1H), 7.41(d, J = 2.4 Hz, 1H), 7.39 (s 1H), 7.34 (d, J = 8.8 Hz, 1H), 4.38 (s, 2H)4.24 (s, 2H), 4.0-3.9 (m, 1H), 3.67-3.61 (m, 1H), 3.19 (s, 3H), 2.69(bs, 5H), 2.35-2.31 (m, 2H), 1.86 (s, 3H) 1157

MS (ESI) m/z 789.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H),8.87 (d, J = 4.8 Hz, 1H), 8.60 (m, 1H), 8.58 (s, 1H), 7.60 (dd, J = 8.8,2.4 Hz, 1H), 7.54 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.38(d, J = 9.2 Hz, 1H), 4.39 (t, J = 6.0 Hz, 2H), 4.35-4.25 (m, 1H), 4.19(t, J = 6.0 Hz, 2H), 3.58 (s, 3H), 3.40- 3.20 (m, 2H), 3.07 (s, 5H),2.65-2.55 (m, 2H), 1.99-1.90 (m, 2H), 1.85-1.79 (m, 2H), 1.74 (s, 1160

MS (ESI) m/z 692.45 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.05 (bs,1H), 8.83 (s, 1H), 8.75 (d, J = 4.6 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J =8.2 Hz, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.52 (d, J = 4.5 Hz, 1H), 4.83(s, 2H), 4.31 (bs, 1H), 3.43 (bs, 7H), 2.85 (s, 4H), 2.11 (s, 3H) 1161

MS (ESI) m/z 708.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.76 (dd, J = 8.3, 0.5 Hz, 1H),7.71-7.65 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H), 4.53 (s, 2H),4.06-2.83 (m, 8H), 2.13 (s, 3H) 1162

MS (ESI) m/z 636.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.18 (bs,1H), 8.84 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J =8.4 Hz, 1H), 7.70-7.65 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H),4.38 (m, 2H), 3.79 (m, 2H,), 3.49 (m, 4H), 3.03 (m, 1H), 2.14 (s, 3H),0.93 (m, 4H) 1163

MS (ESI) m/z 686.0 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H),8.83 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.70-7.66 (m, 1H), 7.53 (d, J = 4.8 Hz, 1H), 4.72 (s, 2H), 3.80(bs, 4H), 3.39 (bs, 4H), 3.05-3.02 (m, 5H), 2.16 (s, 3H) 1164

MS (ESI) m/z 694.52 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz,1H), 7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.36 (d, J =8.8 Hz, 1H), 4.72- 4.54 (m, 2H), 4.39 (bs, 2H), 4.22 (bs, 2H), 3.25-2.78 (m, 10H), 1.81 (s, 3H), 1.45 (bs, 3H) 1165

MS (ESI) m/z, 714.50 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 9.80 (bs,1H), 8.76 (s, 1H), 8.75 (s, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.70-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.56 (bs,1H), 3.56 (bs, 4H), 3.11 (bs, 1H), 3.06 (s, 3H), 3.05 (bs, 4H), 2.13(bs, 4H), 2.11 (s, 3H) 1166

MS (ESI) m/z 714.58 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.76-8.74 (m,2H), 8.65 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70-7.67 (m, 2H), 7.55 (d,J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.58-4.38 (m, 2H), 3.11 (s, 3H),2.90-2.88 (m, 2H), 2.50-2.32 (m, 4H), 2.20-2.15 (m, 5H), 2.12-2.10 (m,2H) 1167

MS (ESI) m/z 668.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.08 (bs,1H), 10.22 (bs, 1H), 8.85 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 8.65 (s,1H), 7.76 (d, J = 8.4 Hz, 1H), 7.69-7.66 (m, 2H), 7.53 (d, J = 4.8 Hz,1H), 4.83 (s, 2H), 4.39 (d, J = 11.6 Hz, 2H), 3.76 (bs, 6H), 3.43 (bs,2H), 2.14 (s, 3H), 1.29 (d, J = 18.8 Hz, 2H), 0.99 (d, J = 7.6 Hz, 2H)1168

MS (ESI) m/z 722.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz,1H), 7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.36 (d, J =9.2 Hz, 1H), 4.52 (bs, 1H), 4.39 (s, 2H), 4.21 (s, 2H), 3.90-3.82 (m,1H), 3.36-3.31 (m, 6H), 3.09 (s, 3H), 2.33- 2.27 (m, 1H), 2.02-2.07 (m,4H), 1.79 (s, 3H), 0.99 (t, J = 7.2 Hz, 3H) 1169

MS (ESI) m/z 696.24 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.76-8.75 (m,2H), 8.64 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.69-7.67 (m, 2H), 7.54 (d,J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.54 (s, 1H), 3.74-3.72 (m, 4H),3.31-3.29 (m, 2H), 3.12 (s, 3H), 2.28-2.22 (m, 2H), 2.13-2.10 (m, 5H),1.25 (d, J = 19.6 Hz, 2H), 0.96 (d, J = 8.0 Hz, 2H) 1170

MS (ESI) m/z 736.43 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.76-.8.74 (m,2H), 8.64 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70-7.67 (m, 2H), 7.54 (d,J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.56-4.52 (m, 3H), 3.67-3.55 (m, 4H),3.25-3.19 (m, 2H), 3.11 (s, 3H), 2.23-2.20 (m, 2H), 2.17- 2.10 (m, 5H)1171

MS (ESI) m/z 664.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =6.0 Hz, 2H), 8.65 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70-7.67 (m, 2H),7.55 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.60-4.59 (m, 1H), 3.66 (d, J =11.6 Hz, 2H), 3.43-3.22 (m, 2H), 3.09 (s, 3H), 2.85 (bs, 1H), 2.10 (s,7H), 0.95-0.85 (m, 4H) 1172

MS (ESI) m/z 744.02 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.76-8.74 (m,2H), 8.64 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.70-7.67 (m, 2H), 7.54 (d,J = 4.8 Hz, 1H), 6.89-6.52 (m, 1H), 4.82 (s, 2H), 4.58-4.45 (m, 2H),3.48-3.38 (m, 5H), 3.10 (s, 3H), 3.08-3.06 (m, 2H), 2.40.2.38 (m, 2H),2.20-2.10 (m, 5H) 1173a

MS (ESI) m/z 762.47 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.77-8.75 (m,2H), 8.65 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H),7.68 (s, 1H), 7.56 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.73 (quin, J =7.2 Hz, 1H), 4.59 (bs, 1H), 3.62 (bs, 4H), 3.41 (bs, 1H), 3.12 (bs, 5H),2.89 (bs, 2H), 2.11 (bs, 7H) 1173b

MS (ESI) m/z 671.41 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.68 (d, J = 1.6 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H),7.70-7.67 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 3H), 3.38-3.28 (m,4H), 3.11 (s, 9H), 2.02 (s, 3H), 1.97-1.91 (m, 2H), 1.89-1.83 (m, 2H)1174

MS (ESI) m/z 710.42 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 9.40 (bs, 1H),8.76-8.74 (m, 2H), 8.64 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70-7.67 (m,2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.56-4.53 (m, 1H),3.94-3.80 (m, 4H), 3.66-3.59 (m, 4H), 3.11 (s, 3H), 2.40-2.34 (m, 3H),2.27-2.24 (m, 1H), 2.10-2.01 (m, 5H), 1.91-1.88(m, 1H), 1.70-1.63(m, 1H)1175

MS (ESI) m/z 732.40 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77-8.74 (m,2H), 8.65 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H),7.68 (s, 1H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.48 (bs, 1H),3.65 (m, 4H), 3.10 (s, 3H), 2.50-2.39 (m, 2H), 2.09 (s, 3H), 2.04 (bs,4H), 1.44-1.33 (m, 2H) 1176

MS (ESI) m/z 720.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.4 Hz, 1H), 8.74 (s, 1H), 8.67 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H),7.69-7.67 (m, 2H), 7.56 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.18-4.15 (m,1H), 3.67-3.64 (m, 2H), 3.29 (bs, 2H), 3.07 (d, J = 9.2 Hz, 2H),2.60-2.55 (m, 2H), 2.06 (s, 3H), 1.96-1.94 (m, 2H), 1.85-1.82 (m, 2H),1.11 (t, J = 6.8 Hz, 3H) 1177

MS (ESI) m/z 716.60 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.14 (bs,1H), 8.77 (d, J = 4.4 Hz, 2H), 8.66 (s, 1H), 7.77-7.74 (m, 1H),7.69-7.68 (m, 2H), 7.56 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.39 (bs,1H), 3.63 (bs, 4H), 3.30 (bs, 4H), 2.34 (bs, 2H), 2.08 (s, 5H), 1.75 (t,J = 18.0 Hz, 3H), 1.13 (t, J = 6.8 Hz, 3H) 1180

MS (ESI) m/z 713.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.62 (bs, 1H),8.79 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.0Hz, 1H), 7.70-7.68 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H),4.41-4.39 (d, J = 12.8 Hz, 2H), 3.83-3.69 (m, 4H), 3.23-3.14 (m, 4H),2.43 (m, 2H), 2.33-2.25 (m, 3H), 2.10 (s, 3H), 1.91-1.88 (m, 2H) 1181

MS (ESI) m/z 696.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.74 (bs, 1H),8.78-8.72 (m, 2H), 8.64 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.70-7.62 (m,2H), 7.55 (d, J = 4.8 Hz, 1H), 5.35-5.18 (m, 1H), 4.82 (s, 2H),4.60-4.52 (m, 1H), 4.04-3.98 (m, 1H), 3.60-3.50 (m, 2H), 3.15-2.95 (m,5H), 2.80-2.45 (m, 4H), 2.20-2.00 (m, 7H) 1182

MS (ESI) m/z 730.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz 1H), 8.71 (s, 1H), 8.65 (s, 1H), 7.76-7.74 (m, 1H), 7.69-7.67 (m,2H), 7.55 (d, J = 4.8 Hz, 1H), 6.46 (t, J = 54.4 Hz, 1H), 4.81 (s, 2H),4.50 (d, J = 6.8 Hz, 2H), 4.44 (d, J = 6.4 Hz, 2H), 4.32- 4.28 (m, 1H),3.16 (s, 3H), 2.91-2.89 (m, 2H), 2.59-2.53 (m, 2H), 2.05 (s, 3H),1.89-1.86 (m, 4H) 1183

MS (ESI) m/z 821.52 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H),8.82 (d, J = 4.8 Hz, 1H), 8.75 (d, J = 2.4 Hz, 2H), 7.77 (d, J = 8.8 Hz,1H), 7.71-7.68 (m, 2H), 7.62 (d, J = 4.8 Hz, 1H), 5.21 (quin, J = 7.6Hz, 1H), 4.97- 4.90 (m, 4H), 4.82 (s, 2H), 4.59 (m, 1H), 3.69- 3.49 (m,4H), 3.11 (bs, 5H), 2.32 (m, 2H), 1.98 (m, 2H), 1.93 (s, 3H), 1.76 (t, J= 19.6 Hz, 3H) 1184

MS (ESI) m/z 728.48 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) 613.11 (bs, 1H),8.78-8.76 (m, 2H), 8.65 (s, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.70-7.68 (m,2H), 7.56 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.37 (bs, 1H), 3.75- 3.59(m, 5H), 3.05 (bs, 6H), 2.15 (bs, 4H), 2.10 (s, 3H), 1.16 (t, J = 6.4Hz, 3H) 1185

MS (ESI) m/z 712.32 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.09 (bs,1H), 8.76-8.74 (m, 2H), 8.64 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H),7.70-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.82-4.75 (m, 6H), 4.55(bs, 1H), 3.91-3.85 (m, 2H), 3.52-3.35 (m, 4H), 3.10 (s, 3H), 2.32-2.21(m, 2H), 2.09 (bs, 5H) 1186

MS (ESI) m/z 694.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J =2.8 Hz, 1H), 8.76 (s, 1H), 8.65 (s, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.69(d, J = 6.8 Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.75 (bs,4H), 4.38 (bs, 2H), 3.61 (d, J = 6.8 Hz, 2H), 3.52 (bs, 2H), 3.16 (bs,2H), 2.16-2.10 (m, 7H), 1.15 (t, J = 6.8 Hz, 3H) 1187

MS (ESI) m/z 715.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.8 Hz, 1H), 8.73 (s, 1H), 8.63 (s, 1H), 7.75 (d, J = 8.8, 1H),7.68-7.68 (m, 2H), 7.63 (d, J = 4.8 Hz, 1H), 6.69 (t, J = 75.2 Hz, 1H),4.81 (s, 2H), 4.70 (t, J = 5.6 Hz, 1H), 4.04 (d, J = 13.2 Hz, 2H), 3.60(t, J = 6.4 Hz, 2H), 3.32-3.27 (m, 2H), 3.00 (t, J = 6.8 Hz, 2H), 2.37(bs, 1H), 2.05 (s, 3H), 1.80 (d, J = 10.4 Hz, 2H), 1.39-1.32 (m, 2H)1188

MS (ESI) m/z 791.62 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H),8.81-8.78 (m, 3H), 7.77 (d, J = 8.40 Hz, 1H), 7.71-7.67 (m, 2H), 7.62(d, J = 4.80 Hz, 1H), 4.83 (s, 2H), 4.59 (bs, 1H), 3.74-3.54 (m, 6H),3.08 (s, 3H), 2.98-2.88 (m, 6H), 2.11-2.05 (m, 4H), 2.00 (s, 3H) 1189

MS (ESI) m/z 758.56 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76-8.74 (m,2H), 8.64 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.70-7.67 (m, 2H), 7.55 (d,J = 4.8 Hz, 1H), 6.65 (t, J = 74.4 Hz, 1H), 4.82 (s, 2H), 4.57-4.47 (m,2H), 3.53 (d, J = 11.6 Hz, 2H), 3.23-3.10 (m, 7H), 2.54- 2.49 (m, 2H),2.32-2.28 (m, 1H), 2.16-2.09 (m, 7H), 2.06-1.91 (m, 2H) 1190

MS (ESI) m/z 716.53 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.09 (bs,1H), 9.32 (bs, 1H), 8.76-8.74 (m, J = 7.8 Hz, 2H), 8.64 (s, 1H) 7.75 (d,J = 8.2 Hz, 1H), 7.71-7.65 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.82 (s,2H), 4.60-4.50 (m, 1H), 3.69 (d, J = 10.4 Hz, 2H), 3.30-311 (m, 4H),3.10 (s, 3H), 2.50-2.32 (merged, 2H), 2.20-2.05 (m, 7H), 1.70 (t, J =19.2 Hz, 3H) 1191

MS (ESI) m/z 752.52 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H),8.77-8.741 (m, 2H), 8.66 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.68 (d, J =6.0 Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 6.57 (t, J = 52.0 Hz, 1H), 4.81(s, 2H), 4.29 (bs, 1H), 3.64 (d, J = 6.8 Hz, 2H), 3.03 (bs, 4H), 2.50(s, 2H), 2.06 (s, 3H), 1.98-1.84 (m, 4H), 1.13-1.08 (m, 3H) 1194

MS (ESI) m/z 602.22 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.62 (bs,1H), 9.01 (s, 1H), 8.41 (s, 1H), 7.62-7.57 (m, 2H), 7.41 (d, J = 2.4 Hz,1H), 7.39 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 4.38 (s, 2H), 4.24 (s, 2H),4.19-4.15 (m, 1H), 3.56 (bs, 1H), 2.68-2.62 (m, 5H), 2.32- 2.27 (m, 2H),1.84 (s, 3H) 1195

MS (ESI) m/z 720.41 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.56 Hz, 1H), 8.68 (s, 1H), 8.59 (s, 1H), 7.74 (d, J = 8.12 Hz, 1H),7.67-7.64 (m, 2H), 7.43 (d, J = 4.64 Hz, 1H), 4.80 (s, 2H), 4.29-4.23(m, 1H), 3.83 (s, 3H), 3.21 (q, J = 10.08 Hz, 2H), 3.10 (s, 3H), 3.04(d, J = 11.4 Hz, 2H), 2.54 (bs, 2H), 2.03 (s, 3H), 1.98-1.89 (m, 2H),1.78 (d, J = 10.52 Hz, 2H) 1196

MS (ESI) m/z 644.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.39 (bs,1H), 8.62 (s, 1H), 7.59 (dd, J = 2.48, 8.88 Hz ,1H), 7.40-7.38 (m, 2H),7.35 (d, J = 8.92 Hz, 1H), 4.63-4.59 (m, 2H), 4.47 (bs, 2H), 4.39 (t, J= 4.64 Hz, 2H), 4.23 (t, J = 4.64 Hz, 3H), 2.82 (bs, 6H), 2.70 (s, 3H),2.54 (s, 3H), 1.94 (s, 3H) 1198

MS (ESI) m/z 620.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.63 (bs, 1H)8.55 (s, 1H), 7.59 (dd, J = 8.88, 2.62 Hz, 1H), 7.42 (t, J = 6.0 Hz,2H), 7.35 (d, J = 8.8 Hz, 1H), 4.40 (d, J = 4.4 Hz, 2H), 4.26 (s, 2H),4.26 (t, J = 4.8 Hz, 2H), 2.98- 3.04 (m, 2H), 2.55 (d, J = 4.0 Hz, 1H),1.93 (s, 3H), 1.13-1.36 (m, 7H) 1199

MS (ESI) m/z 629.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.69 (bs,1H), 8.49 (s, 1H), 7.59 (dd, J = 8.88, 2.62 Hz, 1H), 7.36- 7.43 (m, 3H),4.41 (t, J = 6.0 Hz, 2H), 4.20 (t, J = 6.0 Hz, 2H), 4.26 (t, J = 4.8 Hz,2H), 3.34 (s, 6H), 2.96- 3.01 (m, 2H), 2.40 (d, J = 4.0 Hz, 1H), 1.81(s, 3H), 1.31 (t, J = 12.8 Hz, 3H), 1.03- 1.12 (m, 4H) 1202

MS (ESI) m/z 656.33 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 14.39 (bs, 1H),10.23 (bs, 1H), 8.68 (s, 1H), 7.59 (d, J = 8.0, 2.4 Hz, 1H), 7.45-7.38(m, 2H), 7.39 (d, J = 8.8 Hz, 1H), 4.87 (d, J = 4.8 Hz, 2H), 4.39 (bs,2H), 4.23 (bs, 2H), 3.91-3.82 (m, 2H), 3.60-3.49 (m, 2H), 3.00-2.88 (m,2H), 2.75 (s, 3H), 2.70 (s, 3H), 2.53 (s, 3H), 1.86 (s, 3H) 1203

MS (ESI) m/z 656.33 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 14.39 (bs, 1H),10.23 (bs, 1H), 8.68 (s, 1H), 7.59 (d, J = 8.0, 2.4 Hz, 1H), 7.45-7.38(m, 2H), 7.39 (d, J = 8.8 Hz, 1H), 4.87 (d, J = 4.8 Hz, 2H), 4.39 (bs,2H), 4.23 (bs, 2H), 3.91-3.82 (m, 2H), 3.60-3.49 (m, 2H), 3.00-2.88 (m,2H), 2.75 (s, 3H), 2.70 (s, 3H), 2.53 (s, 3H), 1.86 (s, 3H) 1204

MS (ESI) m/z 554.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H),8.99 (s, 1H), 7.37 (s, 1H), 7.31-7.28 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H),7.14 (d, J = 9.2 Hz, 1H), 6.92 (s, 1H), 6.38 (bs 1H), 4.33 (bs, 2H),4.30 (bs, 2H), 3.80 (s, 2H), 2.60 (t, J = 3.6 Hz, 1H), 2.18 (s, 3H),1.21 (d, J = 7.6 Hz, 2H), 1.12 (bs, 2H) 1216

MS (ESI) m/z 641.37 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.75 (bs,1H), 8.84 (s, 1H), 8.31 (s, 1H), 7.60 (dd, J = 2.52, 8.88 Hz, 1H), 7.45(s, 1H), 7.41 (d, J = 2.48 Hz, 1H), 7.36 (d, J = 8.96 Hz, 1H), 4.39 (t,J = 4.40 Hz, 2H), 4.26 (t, J = 4.44 Hz, 2H), 3.84 (bs, 2H), 3.52 (bs,2H), 3.31 (s, 3H), 3.01 (q, J = 7.48 Hz, 2H), 2.97 (bs, 1H), 2.91 (bs,2H), 1.97 (s, 3H), 1.36 (t, J = 7.56 Hz, 3H) 1217

MS (ESI) m/z 706.31 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.43 (bs,1H), 8.59 (s, 1H), 8.16 (d, J = 3.6 Hz, 2H), 7.59 (dd, J = 2.0, 7.2 Hz,1H), 7.54 (bs, 3H), 7.41 (bs, 3H), 4.45 (bs, 4H), 4.27 (bs, 2H), 3.60(bs, 2H), 3.48 (bs, 2H), 3.33 (bs, 2H), 2.90 (s, 3H), 2.66 (bs, 3H),2.008 (s, 3H) 1219

MS (ESI) m/z 656.26 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H),8.41 (s, 1H), 7.58 (dd, J = 2.48, 8.92 Hz, 1H), 7.42 (m, 2H), 7.35 (d, J= 8.9 Hz, 1H), 4.39-4.37 (m, 2H), 4.20-4.19 (m, 2H), 3.36-3.33 (m, 1H),3.13-3.07 (m, 1H), 3.01 (q, J 7.5 Hz, 2H), 2.75-2.72 (m, 2H), 2.32 (s, 3H), 2.20-2.15 (m, 1H), 1.75 (s, 3H), 1.34 (t, J = 7.5 Hz, 3H), 0.70-0.65(m, 2H), 0.55-0.70 (m, 2H) 1220

MS (ESI) m/z 642.25 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.76 (bs,1H), 9.42 (bs, 2H), 8.62 (s, 1H), 8.41 (s, 1H), 7.60 (dd, J = 2.4, 8.8Hz, 1H), 7.46 (s, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.8 Hz,1H), 4.44-4.40 (m, 3H), 4.22 (s, 2H), 3.51-3.38 (m, 1H), 3.41- 319 (m,2H), 3.04 (m, 3H), 1.83 (s, 3H), 1.36 (m, 4H), 0.84 (m, 1H) 1227

MS (ESI) m/z 638.14 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.56 (bs,1H), 9.65 (bs, 1H), 9.01 (s, 1H), 8.45 (s, 1H), 7.59 (dd, J = 2.4, 8.8Hz, 1H), 7.42 (d, J = 2.4 Hz, 2H), 7.36-7.32 (m, 2H), 7.28-7.23 (m, 2H),4.41 (bs, 2H), 4.26 (bs, 2H), 2.70 (s, 3H), 2.16 (s, 3H), 1.38 (s, 3H)1229

MS (ESI) m/z 698.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.59 (bs, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 7.75 (d, J = 9.2Hz, 1H), 7.70-7.65 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.90-4.79 (m, 4H),4.40-4.29 (m, 1H), 3.65-3.35 (m, 3H), 3.09 (s, 3H), 2.85-2.80 (m, 3H),2.18-1.65 (m, 11H) 1231

MS (ESI) m/z 592.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79-8.77 (m,2H), 8.15 (s, 1H), 7.57 (dd, J = 2.60, 8.84 Hz, 1H), 7.34-7.32 (m, 3H),4.38 (t, J = 4.60 Hz, 2H), 4.26 (t, J = 4.56 Hz, 2H), 1.77 (s, 3H), 1.63(s, 9H) 1232

MS (ESI) m/z 615.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H),8.34 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.47 (s, 1H), 7.44 (d,J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 4.40-3.79 (m, 10H), 3.05-3.00(m, 2H), 2.95 (s, 3H). 1.83 (s, 3H), 1.38-1.34 (t, J = 7.6 Hz, 3H) 1233

MS (ESI) m/z 586.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H),8.68 (d, J = 4.80 Hz, 1H), 8.51 (s, 1H), 7.74 (d, J = 8.40 Hz, 1H),7.67-7.63 (m, 3H), 7.40 (d, J = 4.80 Hz, 1H), 4.88 (s, 2H), 2.18 (s,3H), 1.59 (s, 9H) 1234

MS (ESI) m/z 631.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H),8.49 (s, 1H), 7.59 (dd, J = 8.88, 2.50 Hz, 1H), 7.41 (d, J = 2.60 Hz,1H), 7.40 (s, 1H), 7.35 (d, J = 8.96 Hz, 1H), 4.37 (t, J = 5.00 Hz, 2H),4.19 (t, J = 5.00 Hz, 2H), 4.11 (bs, 1H), 3.92-3.70 (m, 4H), 3.29 (s,3H), 2.70 (s, 3H), 2.11-2.04 (m, 2H), 1.81 (s, 3H) 1235

MS (ESI) m/z 631.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.76 (s, 1H),8.54 (s, 1H), 8.48 (s, 1H), 7.59 (dd, J = 8.8 Hz, 2.4 Hz, 1H) 7.43 (s,2H), 7.35 (d, J = 8.8 Hz, 1H), 5.07 (d, J = 2.8 Hz, 1H), 4.41 (bs, 1H),4.37-4.36 (m, 2H), 4.42 (m, 2H), 3.93-3.87 (m, 2H), 3.79-3.75 (m, 1H),3.59 (d, J = 11.2 Hz, 1H), 3.01 (q, J = 7.6 Hz, 2H), 2.04-2.01 (m, 1H),1.93 (bs, 1H), 1.75 (s, 3H),1.35 (t, J = 7.6 Hz, 3H) 1236

MS (ESI) m/z 631.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.35 (bs,1H), 8.53 (s, 1H), 7.58 (dd, J = 8.96, 2.36 Hz, 1H), 7.39-7.34 (m, 3H),4.45-4.36 (m, 3H), 4.21 (t, J = 4.24 Hz, 2H), 3.92-3.86 (m, 2H),3.78-3.68 (m, 2H), 3.56 (d, J = 12.04 Hz, 1H), 2.70 (s, 3H), 2.53 (s,3H), 2.22-1.86 (m, 5H) 1257

MS (ESI) m/z 572.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H),8.65 (d, J = 4.8 Hz, 1H), 7.71 (d, J = 5.2 Hz, 1H), 7.55 (dd, J = 8.8,2.8 Hz, 1H), 7.44 (d, J = 5.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.31(d, J = 9.2 Hz, 1H), 7.21 (d, J = 4.4 Hz, 1H), 4.36-4.23 (m, 6H), 3.60(d, J = 12.0 Hz, 2H), 3.41 (t, J = 11.6 Hz, 2H), 3.29-3.16 (m, 2H), 2.90(s, 3H), 1.81 (s, 3H) 1258

MS (ESI) m/z 559.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H),8.65 (d, J = 3.8, 1H), 7.75 (d, J = 4.76, 1H), 7.55-7.53 (m, 1H), 7.47(d, J = 5.0 Hz, 1H), 7.39 (s, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.21 (d, J= 3.6 Hz, 1H), 5.07 (s, 1H), 4.41 (s, 1H), 4.35 (t, J = 3.6 Hz, 2H),4.19 (t, J = 5.6 Hz, 2H), 3.89 (t, J = 5.9 Hz, 2H), 3.77-3.73 (m, 1H),3.58 (d, J = 11.4 Hz, 1H), 2.00-1.98 (m, 1H), 1.93 (bs, 1H), 1.74 (s,3H) 1264

MS (ESI) m/z 633.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.37 (s, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.48(d, J = 4.8 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 4.41 (t, J= 5.2 Hz, 2H), 4.27 (t, J = 4.0 Hz, 2H), 3.52 (bs, 6H), 3.77-3.25 (m,2H), 2.92 ( d, J = 3.2 Hz, 3H), 1.82 (s, 3H) 1265

MS (ESI) m/z 642.16 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H),8.80 (d, J = 4.8 Hz,1H), 8.55 (s, 1H), 7.57 (dd, J = 2.4, 8.8 Hz, 1H),7.45 (d, J = 4.8 Hz, 1H), 7.40-7.36 (m, 2H), 4.55 (s, 2H), 4.48 (d, J =14 Hz, 4H), 4.40 (s, 2H), 4.22 (d, J = 14.4 Hz, 4H), 2.85 (d, J = 4 Hz,3H), 2.60 (s, 3H), 1.86 (s, 3H) 1266

MS (ESI) m/z 629.0 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =4.8 Hz, 1H), 8.55 (s, 1H), 8.49 (bs, 2H), 7.57 (dd, J = 2.4, 8.8 Hz,1H), 7.45 (d, J = 4.8 Hz, 1H), 7.40-7.36 (m, 2H), 4.52 (s, 4H), 4.39(d, J = 4.8 Hz, 2H), 4.22 (d, J = 5.2 Hz, 6H), 2.60 (s, 3H), 1.85 (s,3H) 1268

MS (ESI) m/z 678.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.82 (bs, 1H),8.74 (d, J = 4.8 Hz, 1H), 8.48 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.76(s, 1H), 7.56 (dd, J = 8.8, 2.4 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.34(d, J = 8.9 Hz, 1H), 7.28 (d, J = 4.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H),4.43-4.36 (m, 2H), 4.27-4.17 (m, 4H), 3.86 (s, 3H), 3.62-3.53 (m, 2H),3.41-3.29 (m, 2H), 3.21-3.10 (m, 2H), 2.90 (s, 3H), 1.78 (s, 3H) 1273

MS (ESI) m/z 624.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.00 (bs,1H), 8.76 (d, J = 4.80 Hz, 1H), 8.66 (s, 1H), 7.76-7.64 (m, 3H), 7.53(d, J = 4.80 Hz, 1H), 4.82 (s, 2H), 4.38- 4.35 (m, 2H), 3.63-3.60 (m,2H), 3.48-3.25 (m, 4H), 2.91 (s, 3H), 2.73 (s, 3H), 2.14 (s, 3H) 1274

MS (ESI) m/z 680.33 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.72 Hz, 1H), 8.52 (s, 1H), 7.59 (dd, J = 8.88, 2.44 Hz, 1H), 7.44 (d, J= 4.68, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.36 (d J = 9.0 Hz, 1H),6.35-6.05 (m, 1H), 4.40 (t, J = 4.48 Hz, 2H), 4.20 (t, J = 4.72 Hz, 2H),3.64 (s, 4H), 2.87-2.878 (m, 2H), 2.71 (s, 4H), 2.63 (s, 3H), 1.78 (s,3H) 1279

MS (ESI) m/z 622.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H),8.82 (d, J = 4.8 Hz, 1H), 8.39 (s, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz,1H), 4.45-4.36 (m, 2H), 4.30-4.20 (m, 2H), 4.15-4.00 (m, 1H), 2.70-2.50(m, 2H), 2.44-2.20 (m, 3H), 2.14-2.01 (m, 1H), 1.84 (s, 3H) 1281

MS (ESI) m/z 687.47 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 10.05 (bs,1H), 8.87 (d, J = 3.2 Hz, 1H), 8.74 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H),8.47 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 2H), 7.66(s, 1H), 7.49 (d, J = 4.4 Hz, 1H), 6.53 (tt, J = 5.2, 51.2 Hz, 1H), 4.82(s, 2H), 4.49 (bs, 1H), 3.64 (bs, 4H), 3.38 (bs, 2H), 3.16 (s, 3H), 2.17(bs, 2H), 2.04 (bs, 5H) 1282

MS (ESI) m/z 630.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.09 (bs,1H), 8.77 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 7.59 (dd, J = 8.8, 2.4 Hz,1H), 7.48 (d, J = 4.8 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.35 (d, J =9.2 Hz, 1H), 4.39 (s, 2H), 4.21 (s, 2H), 3.64 (s, 4H), 2.55-2.35 (m,7H), 2.23 (s, 3H), 1.83 (s, 3H) 1297

MS (ESI) m/z 644.30 [M + 1]+; 1 H NMR (400 MHz, DMSO-d6) δ 13.46 (bs,1H), 8.66 (d, J = 4.8 Hz, 1H), 7.55 (dd, J = 8.8, 2.4 Hz, 1H), 7.37-7.28(m, 3H), 4.42-4.34 (m, 2H), 4.21 (s, 2H), 3.63 (bs, 4H), 2.64 (s, 3H),2.49-2.35 (m, 7H), 2.22 (s, 3H), 1.84 (s, 3H) 1301

MS (ESI) m/z 628.33 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.82 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.67 (s, 1H), 8.46 (s, 1H), 7.60 (dd, J =8.8, 2.4 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H),7.37 (d, J = 8.8 Hz, 1H), 4.48- 4.40 (m, 3H), 4.29-4.19 (m, 2H),3.45-3.19 (m, 3H), 3.10-2.89 (m, 5H), 1.80 (s, 3H), 1.48-1.27 (m, 2H)1302

MS (ESI) m/z 648.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.15 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 7.57 (dd, J =2.4, 8.8 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.41-7.36 (m, 2H), 4.95 (s,1H), 4.84 (s, 1H), 4.39 (d, J = 4.4 Hz, 2H), 4.30 (d, J = 7.6 Hz, 2H),4.23 (s, 2H), 3.83-3.59 (m, 4H), 3.53- 3.34 (m, 4H), 1.83 (s, 3H) 1303

MS (ESI) m/z 666.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz,1H), 7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.37-7.35 (m,1H), 6.46 (t, J = 54.8 Hz, 1H), 4.41-4.38 (m, 2H), 4.28-4.22 (m, 2H),3.87-3.83 (m, 4H), 3.38-3.32 (m, 2H), 3.24-3.11 (m, 4H), 1.80 (s, 3H)1304

MS (ESI) m/z 684.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 11.77 (bs,1H), 8.81 (d, J = 4.8 Hz, 1H), 8.66 (s, 1H), 8.40 (s, 1H), 7.58 (dd, J =9.2, 6.8 Hz, 1H), 7.45-7.40 (m, 2H), 7.34 (d, J = 8.8 Hz, 1H), 4.37 (s,2H), 4.20 (s, 2H), 3.65 (s, 4H), 3.35-3.20 (m, 2H), 2.81 (s, 4H), 1.75(s, 3H) 1305

MS (ESI) m/z 666 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 4.8Hz , 1H), 8.70 (s, 1H), 8.43 (s, 1H), 7.61 (dd, J = 2.4, 8.8 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.37 (d, J = 8.8 Hz,1H), 6.73-6.46 (m, 1H), 4.39 (s, 2H), 4.34 (s, 1H), 4.23 (s, 2H), 4.18(s, 1H), 3.56-3.15 (m, 5H), 2.83 (s, 3H), 1.82 (s, 3H) 1306

MS (ESI) m/z 642.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.43 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 7.61 (dd, J =8.8 Hz, J = 2.4 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.41-7.38 (m, 2H),4.41-4.40 (m, 4H), 4.31 (t, J = 2.4 Hz, 2H), 3.47 (bs, 6H), 3.01 (bs,1H), 1.85 (s, 3H), 1.00-0.88 (bs, 2H) 1307

MS (ESI) m/z 692.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.31 (bs,1H), 8.82 (d, J = 4.8 Hz, 1H), 8.68 (s, 1H), 8.43 (s, 1H), 7.59 (dd, J =2.40, 8.8 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H),7.36 (d, J = 8.8 Hz, 1H), 4.39 (s, 2H), 4.22 (s, 2H), 3.76 (m, 4H),3.19-2.93 (m, 8H), 2.32 (m, 1H), 1.80 (s, 3H) 1308

MS (ESI) m/z 698.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.33 (bs,1H), 8.82 (d, J = 4.76 Hz, 1H), 8.69 (s, 1H), 8.43 (s, 1H), 7.59 (dd, J= 2.4, 8.8 Hz, 1H), 7.46 (d, J = 4.7 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H),7.35 (d, J = 8.9 Hz, 1H) , 4.39 (t, J = 4.8 Hz, 2H), 4.22 (t, J = 4.4Hz, 2H), 3.38 (bs, 8H), 2.82 (s, 4H), 1.81 (s, 3H) 1309

MS (ESI) m/z 694.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 7.59 (dd, J = 2.4, 8.8 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 9.2 Hz,1H), 6.22 (m, 1H), 4.39 (s, 2H), 4.21 (s, 2H), 3.72 (m, 4H), 2.96 (s,4H), 1.79 (s, 3H), 1.23 (s, 6H) 1310

MS (ESI) m/z 692.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H),7.49 (d, J = 4.80, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz,1H), 6.04 (t, J = 55.6 Hz, 1H), 4.38 (s, 2H), 4.20 (s, 2H), 3.55 (s,4H), 3.01 (s, 4H), 1.75 (s, 3H), 0.90-078 (m, 4H) 1311

MS (ESI) m/z 678.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.66 (s, 1H), 8.45 (s, 1H) 7.60 (dd, J = 9.2 Hz, 2.8 Hz,1H), 7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J =9.2 Hz, 1H), 4.39 (bs, 2H), 4.32 (d, J = 12.8 Hz, 2H), 4.22 (bs, 4H),3.64 (bs, 1H), 3.38 (bs, 1H), 3.19 (bs, 2H), 2.93 (bs, 2H), 2.15 (bs,1H), 1.759 (s, 3H) 1312

MS (ESI) m/z 680.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.22 (bs,1H), 8.82 (d, J = 4.8 Hz 1H), 8.66 (s, 1H), 8.44 (s, 1H), 7.598 (dd, J =2.4, 8.8 Hz, 1H), 7.47 (d, J = 4.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H),7.35 (d, J = 8.8 Hz, 1H), 6.25 (m, 1H), 4.38 (s, 2H), 4.21 (s, 2H), 3.64(m, 4H), 2.97 (m, 4H), 2.63 (s, 1H), 1.77 (s, 3H), 1.16 (s, 3H) 1313

MS (ESI) m/z 658.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.43 (bs, 1H),8.82 (d, J = 4.8 Hz, 1H), 8.70 (s, 1H), 8.41 (s, 1H), 7.60 (dd, J = 8.8Hz, 2.4 Hz, 1H), 7.47 (d, J = 4.4 Hz, 1H), 7.41-7.36 (m, 2H), 4.42-4.39(m, 4H), 4.24 (s, 2H), 3.72 (d, J = 12 Hz, 2H), 3.51 (t, J = 12.4 Hz,2H), 3.19 (d, J = 9.6 Hz, 2H), 1.86 (s, 3H), 1.39 (s, 9H) 1314

MS (ESI) m/z 654.34 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.22 (bs,1H), 8.82 (d, J = 4.7 Hz, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 7.59 (dd, J =8.8, 2.5 Hz, 1H), 7.45 (d, J = 4.7 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H),7.34 (d, J = 9.0 Hz, 1H), 4.41 (s, 4H), 4.36 (s, 2H), 4.18 (s, 2H), 3.49(bs, 4H), 1.90 (bs, 1H), 1.73 (s, 3H), 0.42- 0.20 (m, 4H) 1315

MS (ESI) m/z 698.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.4 Hz, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H),7.49 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz,1H), 4.42-4.34 (m, 2H), 4.20 (s, 2H), 3.63-3.57 (m, 5H), 2.90- 2.80 (m,4H), 1.76 (s, 3H), 1.21 (d, J = 6.8 Hz, 3H) 1316

MS (ESI) m/z 712.41 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz,1H), 4.41-4.35 (m, 2H), 4.23-4.16 (m, 2H), 3.61 (s, 4H), 2.93 (s, 4H),1.75 (s, 3H), 1.32 (s, 6H) 1317

MS (ESI) m/z 676.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.23 (bs,1H), 8.82 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 8.45 (s, 1H), 7.59- 7.57(m, 1H), 7.45 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H), 4.38 (s, 2H), 4.20 (s, 2H), 3.65 (s, 4H), 2.67 (s, 4H),2.60-2.48 (m, 2H), 1.74 (s, 3H), 1.35 (J = 21.6 Hz, 6H) 1318

MS (ESI) m/z 7694.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J =4.8 Hz, 1H), 8.51 (s, 1H), 8.31 (s, 1H), 7.59 (dd, J = 2.4, 8.8 Hz, 1H),7.45 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 9.2 Hz,1H), 6.54 (t, J = 57.2 Hz, 1H), 4.49 (bs, 2H), 4.39 (bs, 2H), 4.21 (bs,2H), 3.60 (bs, 4H), 3.08 (t, J = 12.0 Hz, 2H), 3.08 (s, 3H), 2.17 (bs,1H), 2.03 (bs, 4H) 1.76 (s, 3H) 1319

MS (ESI) m/z 670.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.76 Hz, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 7.60 (dd, J = 8.9 Hz, 2.4 Hz,1H), 7.47 (d, J = 4.7 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.36 (d, J =9.0 Hz, 1H), 4.57- 4.52 (m, 1H), 4.39 (d, J = 5.6 Hz, 2H), 4.17 (d, J =5.28, 2H), 3.65 (d, J = 11.44, 2H), 3.95 (bs, 2H), 3.07 (s, 3H), 2.83(bs, 1H), 2.07 (s, 4H), 1.76 (s, 3H), 0.94-0.85 (m, 4H) 1320

MS (ESI) m/z 686.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H),8.82 (d, J = 4.8, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.59 (dd, J = 2.4,8.8 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36(d, J = 8.8 Hz, 1H), 4.77-4.76 (m, 4H), 4.55 (bs, 1H), 4.39 (s, 3H),4.21 (s, 2H), 3.26-3.15 (m, 2H), 3.09-2.97 (m, 5H), 2.21-2.08 (m, 4H),1.77 (s, 3H) 1321

MS (ESI) m/z 652.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H),6 8.74 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.69-7.66 (m, 2H), 7.53 (d, J = 4.4 Hz, 1H), 4.83 (s, 2H), 4.76 (s, 4H),4.37 (bs, 4H), 4.04 (bs, 1H), 3.34-2.82 (m, 4H), 2.12 (s, 3H) 1322

MS (ESI) m/z 664.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J =4.8 Hz, 1H), 8.70 (s, 1H), 8.64 (s, 1H), 7.76-7.73 (m, 1H), 7.69-7.66(m, 2H), 7.52 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 4.54 (t, J = 6.4 Hz,2H), 4.47 (s, 4H), 4.35 (t, J = 6 Hz, 2H), 3.69 (t, J = 5.6 Hz, 1H),3.42 (s, 4H), 2.0 (s, 3H) 1323

MS (ESI) m/z 630.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H),8.80 (d, J = 4.8 Hz, 1H), 8.59 (s, 1H), 8.50 (s, 1H), 7.59 (dd, J = 2.4,8.8 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.36(d, J = 9.2 Hz, 1H), 7.19 (s, 1H), 4.41 (t, J = 4.8 Hz, 2H), 4.24 (t, J= 4.8 Hz, 2H), 3.64 (s, 2H), 2.96 (m, 5H), 2.5 (m, 3H), 2.10 (m, 2H),1.85 (s, 3H) 1324

MS (ESI) m/z 652.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H),8.85 (d, J = 4.81 Hz, 1H), 8.36 (s, 1H), 7.62-7.59 (m, 2H), 7.47 (d, J =4.8 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.06(bs, 1H), 4.44 (s, 2H), 4.33 (s, 2H), 3.29 (s, 6H), 2.60 (s, 3H), 1.92(s, 3H) 1325

MS (ESI) m/z 652.36 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.23 (bs,1H), 9.09 (s, 1H), 9.00 (s, 1H), 8.85 (d, J = 4.4 Hz, 1H), 8.38 (s, 1H),8.31 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.60 ( dd, J = 8.8,2.4 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.36(d, J = 8.8 Hz, 1H), 4.42 (s, 2H), 4.28 (s, 2H), 3.66 (s, 2H), 2.26 (s,6H), 1.83 (s, 3H) 1326

MS (ESI) m/z 631.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.23 (bs,1H), 8.97 (s, 1H), 8.83 (d, J = 4.8 Hz, 1H), 8.36 (s, 1H), 7.60 (dd, J =9.2, 2.0 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H),7.35 (d, J = 8.8 Hz, 1H), 4.81 (d, J = 46.4 Hz, 2H), 4.47-4.38 (m, 4H),4.26 (s, 2H), 3.65-3.30 (m, 2H), 2.86 (s, 3H), 1.77 (s, 3H) 1327

MS (ESI) m/z 667.38 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.16 (bs,1H), 8.94 (s, 1H), 8.83 (d, J = 4.8 Hz, 1H), 8.38 (s, 1H), 7.59 (dd, J =9.2, 2.4 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H),7.34 (d, J = 8.8 Hz, 1H), 4.39 (s, 2H), 4.25 (s, 2H), 3.88 (s, 2H), (q,J = 10.0 Hz, 2H), 2.54 (s, 3H), 1.73 (s, 3H) 1328

MS (ESI) m/z 633.40 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.40 (bs,1H), 10.08 (bs, 1H), (9.01 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.36 (s,1H), 7.60 (dd, J = 8.9, 2.5 Hz, 1H), 7.48 (d, J = 4.7 Hz, 1H), 7.45-7.33(m, 3H), 7.21-7.18 (m, 1H), 4.88 (d, J = 47.2 Hz, 2H), 4.41 (t, J = 4.9Hz, 2H), 4.27-4.13 (m, 4H), 3.70-3.55 (m, merged, 2H), 2.90 (s, 3H),1.81 (s, 3H) 1329

MS (ESI) m/z 625.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.34 (s, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H),7.48 (d, J = 4.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz,1H), 4.40 (bs, 2H), 4.25 (bs, 2H), 2.74 (bs, 6H), 1.75 (s, 3H), 1.36(bs, 4H) 1330

MS (ESI) m/z 617.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.38 (bs,1H), 10.15 (bs, 1H), 9.02 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.34 (s,1H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 7.43 (d,J = 2.8 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H), 5.27 (d, J = 8.0 Hz, 1H),4.40 (bs, 2H), 4.32-4.23 (m, 2H), 3.94 (t, J = 12.4 Hz, 1H), 3.78 (bs,2H), 3.49 (bs, 2H), 3.24 (bs, 1H), 2.99 (s, 3H), 1.81 (s, 3H) 1332

MS (ESI) m/z 655.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H),8.84 (d, J = 4.8 Hz, 1H), 8.23 (s, 1H), 7.61 (dd, J = 9.2, 2.8 Hz, 1H),7.46 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 9.2 Hz,1H), 4.42 (bs, 2H), 4.30 (bs, 2H), 2.82 (bs, 2H), 2.72 (s, 6H), 2.61(bs, 2H) 1.30 (s, 9H) 1333

MS (ESI) m/z 676.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.33 (bs,1H), 9.75 (bs, 1H), 8.83 (d, J = 4.8 Hz, 1H), 8.71 (s, 1H), 8.38 (s,1H), 7.61-7.58 (dd, J = 2.8, 9.2 Hz, 1H), 7.47 (d, J = 4.4 Hz, 1H), 7.42(d, J = 2.4 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 4.97-4.79 (m, 2H), 4.39(bs, 2H), 4.22 (bs, 2H), 3.88-3.48 (m, 6H), 1.79 (s, 3H), 1.45 (s, 3H),1.40 (s, 3H) 1334

MS (ESI) m/z 684.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H),8.82 (d, J = 4.8 Hz, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 7.59 (d, J = 7.2Hz, 1H), 7.47 (d, J = 4.4 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 9.2 Hz,1H), 4.38 (s, 2H), 4.21 (s, 2H), 4.08 (d, J = 11.2 Hz, 1H), 3.82- 3.05(m, 5H), 2.67 (s, 1H), 2.50 (s, 3H), 1.76 (s, 3H) 1335

MS (ESI) m/z 630.46 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H),8.85 (d, J = 8.4 Hz, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.61 (d, J = 8.8Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.41 (m, 2H), 4.74 (bs, 1H), 4.42 (m,2H), 4.23 (m, 4H), 3.52 (m, 2H), 3.32 (m, 2H). 2.91 (s, 3H), 1.78 (s,3H), 1.49 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 5.6 Hz, 1H) 1336

MS (ESI) m/z 674.50 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 7.60 (dd, J = 9.2, 2.8 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 4.62 (d, J = 49.6 Hz, 2H), 4.40-4.35 (m, 2H), 4.25-4.15 (m, 2H),3.75-3.55 (m, 4H), 3.30-3.00 (m, 4H), 1.79 (s, 3H), 1.15-.0.80 (m, 4H)1337

MS (ESI) m/z 642.53 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.37 (bs,1H), 8.82 (d, J = 4.4 Hz, 1H), 8.70 (s, 1H), 8.38 (s, 1H), 7.60 (t, J =6.8 Hz, 1H), 7.47-7.21 (m, 3H), 4.39 (s, 2H), 4.23 (s, 2H), 4.05 (bs,2H), 3.93 (bs, 2H), 3.52 (bs, 2H), 2.99 (s, 3H), 1.79 (s, 3H), 1.26-1.07 (m, 4H) 1338

MS (ESI) m/z 674.53 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.21 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.68 (s, 1H), 8.39 (s, 1H), 7.60 (dd, J =8.8, 2.0 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H),7.36 (d, J = 8.8 Hz, 1H), 4.83-4.72 (m, 2H), 4.39 (s, 2H), 4.23 (s, 2H),3.98-3.53 (m, 8H), 1.77 (s, 3H), 1.03 (bs, 4H) 1339

MS (ESI) m/z 708.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.27 (bs,1H), 8.82 (d, J = 8.0 Hz, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 7.59 (d, J =6.8 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J = 9.2Hz, 1H), 4.39 (s, 2H), 4.22 (s, 2H), 3.59-3.30 (m, 12H), 3.10 (s, 3H),1.79 (s, 3H) 1340

MS (ESI) m/z 692.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 4.57 (t, J = 8.0 Hz, 2H), 4.38 (bs, 4H), 4.20 (bs, 2H), 3.94 (bs,1H), 3.07 (bs, 4H), 2.20 (bs, 4H), 1.76 (s, 3H) 1341

MS (ESI) m/z 664.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.48 (s, 1H), 7.59 (dd, J =2.4, 8.8 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H),4.47-4.42 (m, 2H), 4.37 (bs, 2H), 4.18 (bs, 2H), 4.13-4.10 (m, 2H),3.95-3.74 (m, 5H), 1.74 (s, 3H) 1342

MS (ESI) m/z 655.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.27 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 7.60 (dd, J =8.8, 2.4 Hz, 1H), 7.46 (d, J = 4.0 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H),7.35 (d, J = 9.2 Hz, 1H), 4.43-4.35 (m, 2H), 4.25-4.15 (m, 2H), 4.13-4.00 (m, 2H), 3.16- 3.10 (m, 1H), 2.97- 2.83 (m, 4H), 2.48-2.33 (m, 2H),2.30 (s, 3H), 1.74 (s, 3H) 1343

MS (ESI) m/z 683.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.69 (s, 1H), 8.43 (s, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.8 Hz,1H), 4.40 (s, 2H), 4.23 (s, 2H), 3.95 (s, 2H), 3.57-3.40 (m, 4H),3.30-3.15 (m, 4H), 1.83 (s, 3H), 1.46 (s, 6H) 1344

MS (ESI) m/z 651.48 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H),8.83 (d, J = 4.4 Hz, 1H), 8.36 (s, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H),7.48 (d, J = 4.4 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 9.2 Hz,1H), 4.80-4.60 (m, 1H), 4.40 (s, 2H), 4.25 (s, 2H), 3.55-3.30 (m,merged, 2H), 2.50-2.30 (m, 1H), 2.22-1.91 (m, 4H), 1.75 (s, 3H),1.04-0.61 (m, 4H) 1345

MS (ESI) m/z 635.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.40 (bs.1H), 9.67 (bs, 1H), 8.96 (s, 1H), 8.82 (d, J = 4.7 Hz, 1H), 8.32 (s,1H), 7.60 (dd, J = 8.92, 2.36 Hz, 1H), 7.47 (d, J = 4.7 Hz, 1H), 7.43(d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.92-4.76 (m, 1H), 4.40(t, J = 4.4 Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H), 3.62-3.52 (m, 2H),3.40-3.20 (m, 2H), 3.18 (t, J = 7.24 Hz, 2H), 2.88 (s, 3H), 2.31-2.17(m, 2H), 1.82 (s, 3H) 1346

MS (ESI) m/z 639.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H),8.83 (d, J = 4.7 Hz, 1H), 8.37 (s, 1H), 7.59 (dd, J = 8.9, 2.4 Hz, 1H),7.47 (d, J = 4.7 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H ), 7.34 (d, J = 9.0Hz, 1H), 4.65-4.35 (m, 4H), 4.25 (t, J = 3.8 Hz, 2H), 2.85 (bs, 3H),1.75 (s, 3H), 1.36 (s, 3H), 1.03 (bs, 2H), 0.72 (bs, 2H) 1347

MS (ESI) m/z 624.49 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.08 (bs,1H), 8.86 (s, 1H), 8.79 (d, J = 4.4 Hz, 1H), 8.66 (s, 1H), 7.88 (d, J =8.4 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 4.8Hz, 1H), 6.52-6.38 (m, 1H), 5.89 (d, J = 16.0 Hz, 1H), 4.68 (d, J = 4.0Hz, 2H), 4.39 (d, J = 13.2 Hz, 1H), 3.11 (t, J = 12.4 Hz, 2H), 2.82-2.65(m, 1H), 2.40-2.10 (m, 8H), 0.72-0.45 (m, 2H) 1348

MS (ESI) m/z 628.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6), 68.81 (d, J =4.8 Hz, 1H), 6 8.62 (s, 1H), 8.43 (s, 1H), 7.59 (dd, J = 8.8 Hz, 2.4 Hz,1H), 7.45-7.42 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 4.78 (bs, 1H), 4.37(t, J = 5.1 Hz, 2H), 4.27 (t, J = 4.5 Hz, 2H), 3.45-3.43 (m, 2H),3.32-2.8 (m, 4H), 2.75-2.56 (m, 2H), 1.93-1.90 (m, 2H), 1.74 (s, 3H)1349

MS (ESI) m/z 715.66 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H),8.82 (d, J = 4.8 Hz, 1H), 8.41 (s, 1H), 7.58 (dd, J = 8.8 Hz, 2.8 Hz,1H), 7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.34 (d, J =8.8 Hz, 1H), 4.38 (s, 2H), 4.22 (s, 2H), 4.05 (s, 1H), 3.40-3.32 (m,2H), 2.93 (s, 2H), 2.66-2.61 (m, 2H), 2.11-2.09 (m, 2H), 1.74 (s, 5H)1350

MS (ESI) m/z 694.59 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.65 (s, 1H), 8.41 (s, 1H), 7.59 (dd, J = 2.0, 8.8 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 6.15 (bs, 1H), 4.39 (s, 2H), 4.21-4.16 (m, 2H), 4.14 (bs, 2H), 3.01(bs, 6H), 1.77 (s, 3H), 1.21 (s, 6H) 1351

MS (ESI) m/z 658.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =2.36 Hz, 1H), 8.74 (s, 1H), 8.40 (s, 1H), 7.60 (dd, J = 8.9, 2.5 Hz,1H), 7.47 (d, J = 4.7 Hz, 1H), 7.42 (d, J = 2.5 Hz, 2H), 7.37 (d, J =9.0 Hz, 2H), 4.66 (d, J = 7.5 Hz, 2H), 4.40 (s, 2H), 4.24 (s, 2H), 4.14(bs, 4H), 3.40 (s, 2H), 3.06 (s, 3H), 1.82 (s, 3H) 1352

MS (ESI) m/z 652.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H),6 8.74 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.69-7.66 (m, 2H), 7.53 (d, J = 4.4 Hz, 1H), 4.83 (s, 2H), 4.76 (s, 4H),4.37 (bs, 4H), 4.04 (bs, 1H), 3.34-2.82 (m, 4H), 2.12 (s, 3H) 1353

MS (ESI) m/z 692.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (bs,1H), 8.83 (s, 1H), 8.75 (d, J = 4.6 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J =8.2 Hz, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.52 (d, J = 4.6 Hz, 1H), 4.83(s, 2H), 4.31 (bs, 1H), 3.43 (bs, 7H), 2.85 (s, 4H), 2.11 (s, 3H) 1354

MS (ESI) m/z 636.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.18 (bs,1H), 8.84 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J =8.4 Hz, 1H), 7.70-7.65 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H),4.38 (m, 2H), 3.79 (m, 2H,), 3.49 (m, 4H), 3.03 (m, 1H), 2.14 (s, 3H),0.93 (m, 4H) 1355

MS (ESI) m/z 686.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H),8.83 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.70-7.66 (m, 1H), 7.53 (d, J = 4.8 Hz, 1H), 4.72 (s, 2H), 3.80(bs, 4H), 3.39 (bs, 4H), 3.05-3.02 (m, 5H), 2.16 (s, 3H) 1356

MS (ESI) m/z 660.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (bs,1H), 8.79 (s, 1H), 8.75 (d, J = 4.6 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J =8.1 Hz, 1H), 7.68 (m, 2H), 7.53 (d, J = 4.6 Hz, 1H), 6.34 (m, 1H), 4.82(s, 2H), 3.76-2.66 (m, 10H), 2.09 (s, 1H) 1357

MS (ESI) m/z 658.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 6.33 (t, J = 53.6 Hz, 1H), 5.09 (s, 1H), 4.38 (t, J = 4.3 Hz, 2H),4.21 (t, J = 5.7, 2H), 4.15-3.80 (m, 7H), 2.21 (bs, 2H), 1.76 (s, 3H)1358

MS (ESI) m/z 716.50 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz,1H), 7.48 (d, J = 4.8 Hz, 1H), 7.37-7.33 (m, 2H), 5.77 (d, J = 46 Hz,1H), 4.39 (s, 2H), 4.22 (s, 2H), 3.24 (bs, 2H), 3.29-3.15 (m, 8H), 1.79(s, 3H) 1359

MS (ESI) m/z 766.56 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 4Hz, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 4.39 (bs, 2H), 4.21 (bs, 2H), 3.68 (bs, 4H), 2.96 (bs, 2H), 2.78(bs, 4H), 2.46 (s, 1H) 1.77 (s, 3H) 1360

MS (ESI) m/z 726.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.53 (bs, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.59 (dd, J = 8.8Hz, 2.4 Hz, 1H), 7.47 (d, J = 4.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H),7.36 (d, J = 8.8 Hz, 1H), 4.49 (bs, 1H), 4.52 (bs, 1H), 4.21 (bs, 2H),3.69 (d, J = 10.4 Hz, 2H), 3.50 (bs, 2H), 3.40 (bs, 2H), 3.21 (s, 3H),2.89-2.85 (m, 2H), 2.11 (bs, 4H), 1.78 (s, 3H) 1361

MS (ESI) m/z 724.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.64 (s, 1H), 8.46 (s, 1H), 7.60 (dd, J = 8.8, 2.8 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz,1H), 4.37 (s, 2H), 4.20 (s, 2H), 3.63 (bs, 4H), 2.84 (bs, 4H), 2.70-2.50(m, 2H), 1.77 (s, 3H), 0.84-0.74 (m, 4H) 1362

MS (ESI) m/z 755.45 [M + 1]+; 1H NMR (400 MHz, DMSO- d6) δ 12.44 (s,1H), 8.83-8.79 (m, 3H), 7.76 (d, J = 8.4 Hz, 1H), 7.71- 7.67 (m, 2H),7.61 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.75- 3.60 (m, 4H), 3.56 (s,3H), 3.31 (q, J = 10.0 Hz, 2H), 2.90-2.80 (m, 4H), 2.00 (s, 3H) 1363

MS (ESI) m/z 668.48 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.21 (bs,1H), 9.37 (bs, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.67 (s, 1H), 8.37 (s,1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.41 (d,J = 2.0 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 4.38 (s, 2H), 4.21 (s, 2H),3.80-3.50 (m, 2H), 3.20-2.90 (m, 2H), 2.61 (s, 3H), 1.78 (s, 3H),1.40-0.80 (m, 8H) 1364

MS (ESI) m/z 642.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 4.87-4.75 (m, 4H), 4.39 (bs, 2H), 4.22 (bs, 2H), 3.56-3.14 (m, 8H),2.41 (s, 1H), 1.78 (s, 3H) 1365

MS (ESI) m/z 656.52 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.30 (bs, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 7.62- 7.59 (dd, J= 2.4, 8.8 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.41-7.36 (m, 2H), 4.40(bs, 4H), 4.24 (bs, 2H), 3.48 (bs, 6H), 1.85 (s, 3H), 1.39 (s, 3H), 1.19(bs, 2H), 0.82 (bs, 2H) 1366

MS (ESI) m/z 686.46 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79-8.73 (m,2H), 8.66 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.72-7.66 (m, 2H), 7.55 (d,J = 4.8 Hz, 1H), 6.04 (t, J = 55.6 Hz, 1H), 4.82 (s, 2H), 3.59 (s, 4H),3.02 (s, 4H), 2.06 (s, 3H), 0.90-0.78 (m, 4H) 1367

MS (ESI) m/z 677.49 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (bs,1H), 9.99 (bs, 1H), 8.82 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s,1H), 7.75 (d, J = 8.4 Hz, 1H), 7.71-7.66 (m, 2H), 7.54 (d, J = 4.8 Hz,1H), 4.83 (s, 2H), 4.45 (bs, 2H), 3.62 (bs, 4H), 3.27 (bs, 4H), 2.13 (s,3H), 1.46 (bs, 6H) 1368

MS (ESI) m/z 661.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H),8.77 (d, J = 3.2 Hz, 1H), 8.67 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H),7.71-7.65 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.67 (s, 4H),2.82 (s, 4H) 2.07 (s, 3H), 1.32-1.27 (m, 2H), 1.17-1.09 (m, 2H) 1369

MS (ESI) m/z 682.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.4 Hz, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 7.60 (dd, J = 9.2, 2.4 Hz, 1H),7.46 (d, J = 4.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 9.2 Hz,1H), 4.60 (s, 2H), 4.52 (s, 2H), 4.43-4.38 (m, 4H), 4.33-4.28 (m, 2H),4.20 (bs, 2H), 3.79 (bs, 1H), 1.89 (t, J = 6.8 Hz, 2H), 1.80 (s, 3H),1.67-1.58 (m, 4H), 1.47 (t, J = 6.4 Hz, 2H) 1370

MS (ESI) m/z 684.53 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.9 Hz, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H),7.46 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 4.51 (bs, 1H), 4.39 (s, 2H), 4.21 (s, 2H), 3.68 (d, J = 10.4 Hz,2H), 3.21-3.16 (m, 2H), 3.09 (s, 3H), 3.01 (t, J = 5.6 Hz, 2H),2.21-2.15 (m, 2H), 2.12-2.06 (m, 2H), 1.77 (s, 3H), 1.10 (bs, 1H), 0.67(d, J = 7.2 Hz , 2H), 0.44-0.38 (m, 2H) 1371

MS (ESI) m/z 654.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.48 (bs,1H), 8.82 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 7.60 (dd, J =9.2, 2.4 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H),7.36 (d, J = 8.8 Hz, 1H), 5.25-4.89 (m, 2H), 4.63 (d, J = 10.4 Hz, 2H),4.38 (s, 2H), 4.21 (s, 2H), 3.98 (bs, 2H), 3.18 (bs, 1H), 2.75 (bs, 2H),1.78 (s, 3H), 0.86 (bs, 4H) 1378

MS (ESI) m/z 608.1 1382

MS (ESI) m/z 608.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400MHz, DMSO- d6) δ 9.05 (s, 1H), 8.44 (s, 1H), 7.94-7.86 (m, 2H),7.64-7.54 (m, 4H), 7.46-7.40 (m, 2H), 7.37 (d, J = 9.0 Hz, 1H), 4.42 (d,J = 4.9 Hz, 2H), 4.29 (d, J = 4.9 Hz, 2H), 2.71 (s, 3H), 1.89 (s, 3H)1390

MS (ESI) m/z 650.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H),8.39 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (d, J = 2.8 Hz, 2H),7.35 (d, J = 9.0 Hz, 1H), 6.29 (s, 1H), 4.39 (d, J = 5.0 Hz, 2H), 4.26(d, J = 4.9 Hz, 2H), 2.91-2.78 (m, 4H), 2.71 (s, 3H), 2.35- 2.15 (m,2H), 1.85 (s, 3H) 1395

MS (ESI) m/z 714.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.8 Hz, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.39 (d, J = 9.0 Hz,1H), 4.54 (s, 2H), 4.43 (t, J = 5.1 Hz, 2H), 4.24 (t, J = 5.1 Hz, 2H),3.82-3.40 (m, 10H), 1.83 (s, 3H) 1396

MS (ESI) m/z 708.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.76 (dd, J = 8.3, 0.5 Hz, 1H),7.71-7.65 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H), 4.53 (s, 2H),4.06-2.83 (m, 8H), 2.13 (s, 3H) 1397

MS (ESI) m/z 708.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.51-7.47 (m, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H),6.46 (t, J = 54.6 Hz, 1H), 4.54 (s, 4H), 4.41 (t, J = 4.9 Hz, 2H), 4.21(t, J = 4.8 Hz, 2H), 4.10 (s, 4H), 2.75 (t, J = 4.7 Hz, 4H), 1.75 (s,3H) 1398

MS (ESI) m/z 650.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H),8.39 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (d, J = 2.8 Hz, 2H),7.35 (d, J = 9.0 Hz, 1H), 6.29 (s, 1H), 4.39 (d, J = 5.0 Hz, 2H), 4.26(d, J = 4.9 Hz, 2H), 2.91-2.78 (m, 4H), 2.71 (s, 3H), 2.35- 2.15 (m,2H), 1.85 (s, 3H) 1399

MS (ESI) m/z 842.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H),8.90 (d, J = 4.9 Hz, 1H), 8.72 (ddd, J = 4.6, 1.7, 0.9 Hz, 1H), 8.65 (s,1H), 8.60 (s, 1H), 8.30-8.25 (m, 1H), 8.21 (td, J = 7.7, 1.7 Hz, 1H),7.80-7.72 (m, 2H), 7.72-7.68 (m, 2H), 7.66 (d, J = 4.8 Hz, 1H), 4.83 (s,2H), 3.09 (s, 3H), 1.94 (s, 3H), 1.77 (t, J = 18.9 Hz, 2H) 1400

MS (ESI) m/z = 740.3 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 6 9.59-9.49 (b,1H), 8.83 (d, J = 4.6 Hz, 1H), 8.70 (s, 1H), 8.42 (s, 1H), 7.61 (dd, J =8.9, 2.7 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H),7.38 (d, J = 8.9 Hz, 1H), 4.43-4.36 (m, 2H), 4.24 (t, J = 4.8 Hz, 2H),3.61-3.49 (m, 2H), 3.34-3.20 (m, 2H), 2.49-2.39 (m, 2H), 2.00-1.92 (m,2H), 1.85 (s, 3H), 1.39 (s, 6H). Remaining protons partially obscured bywater peak 1401

MS (ESI) m/z = 738.3 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 6 8.83 (d, J =4.9 Hz, 1H), 8.67 (s, 1H), 8.42 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.48 (d, J = 4.7 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 8.9 Hz,1H), 4.40 (t, J = 4.9 Hz, 2H), 4.23 (t, J = 4.9 Hz, 2H), 2.39- 2.25 (m,2H), 1.82 (s, 3H), 1.40-0.45 (b, 4H). Remaining protons appear as verybroad signals and/or are partially obscured by water peak 1402

MS (ESI) m/z = 627.3 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 6 10.20-10.10ppm (b, 1H), 9.15 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H),7.78-7.75 (m, 1H), 7.71-7.68 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 7.42 (d,J = 15 Hz, 1H), 7.19 (dt, J = 7.3, 15 Hz, 1H), 4.97-4.79 (m, 2H), 4.88(s, 2H), 4.35-4.13 (m, 2H), 3.75-3.53 (m, 2H), 2.91 (s, 3H), 2.15 (s,3H) 1403

MS (ESI) m/z = 686.2 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 68.77 (d, J =4.8 Hz, 1H), 8.71 (s, 1H), 8.65 (s, 1H), 7.77-7.73 (m, 1H), 7.71-7.66(m, 2H), 7.53 (d, J = 4.8 HZ, 1H), 6.37 (bt, J = 55 Hz, 1H), 4.81 (s,2H), 3.25 (s, 3H), 2.37-2.18 (b, 2H), 2.11 (s, 3H). Remaining protonsare (partially) obscured by water peak 1404

MS (ESI) m/z = 674.4 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 68.75 (s, 1H),8.75 (d, J = 4.7 Hz, 1H), 8.59 (s, 1H), 7.74 (dd, J = 8.1, 0.5 Hz, 1H),7.69-7.64 (m, 2H), 7.43 (dd, J = 4.7, 0.3 Hz, 1H), 6.22 (tt, J = 55.7,4.4 Hz, 1H), 4.81 (s, 2H), 3.85 (s, 3H), 3.71-3.67 (m, 4H), 2.84 (dt, J= 15.7, 4.2 Hz, 2H), 2.78-2.72 (m, 4H), 2.06 (s, 3H) 1405

MS (ESI) m/z = 722.5 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 68.82 (s, 1H),8.74 (d, J = 4.7 Hz, 1H), 8.62 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67(dd, J = 8.4, 2.2 Hz, 1H), 7.61 (dd, J = 2.2, 0.4, 1H), 7.43 (d, J = 4.7Hz, 1H), 4.82 (s, 2H), 4.59-4.53 (m, 2H), 3.86 (s, 3H), 3.69-3.62 (m,2H), 2.16 (s, 3H). Remaining protons appear as very broad signals and/orare partially obscured by water peak 1406

MS (ESI) m/z = 714.5 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 6 10.38-10.18(b, 1H), 8.76 (d, J = 4.7 Hz, 1H), 8.75 (s, 1H), 8.66 (s, 1H), 7.78-7.66(m, 3H), 7.55 (d, J = 4.7 Hz, 1H), 6.59 (t, J = 52.6 Hz, 1H), 4.82 (s,2H), 4.78- 4.68 (m, 1H), 4.24-4.14 (m, overlapping with water peak),3.76-3.58 (m, overlapping with water peak), 3.12 (s, 3H), 2.47-2.37 (m,2H), 2.37-2.26 (m, 2H), 2.21-2.13 (m, 2H), 2.10-2.01 (m, 2H) 1407

MS (ESI) m/z = 686.1 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 68.79 (b, 1H),8.77 (d, J = 4.7 Hz, 1H), 8.67 (s, 1H), 7.79-7.74 (m, 1H), 7.71- 7.67(m, 2H), 7.54 (d, J = 4.7 Hz, 1H), 6.58- 5.69 (b, 1H), 4.84 (s, 2H),3.33 (t, J = 6.6 Hz, 1H), 3.28 (s, 3H), 2.08 (s, 3H). Remaining protonsappear as broad signals and/or are (partially) obscured by water peak1408

MS (ESI) m/z = 819.2 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 6 12.98 (bs,1H), 10.80-10.54 (b, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.79 (s, 1H), 8.75(s, 1H), 7.77 (dd, J = 8.3, 0.5 Hz, 1H), 7.72-7.66 (m, 2H), 7.63 (d, J =4.8 Hz, 1H), 6.40 (tt, J = 53.6, 2.8 Hz, 1H), 5.27-5.17 (m, 1H),5.00-4.90 (m, 4H), 4.82 (s, 2H), 4.12 (bs, 2H), 3.99-3.85 (m, 2H),3.76-3.55 (m, 4H), 2.11-1.93 (m, 4H), 1.96 (s, 3H) 1409

MS (ESI) m/z = 840.5 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 6 13.15-12.95(b, 1H), 10.75- 10.55 (b, 1H), 9.26 (dd, J = 2.4, 0.7 Hz, 1H), 8.89 (dd,J = 4.8, 1.6 Hz, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 8.52 (ddd,J = 8.1, 2.4, 1.6 Hz, 1H), 8.46 (s, 1H), 7.74-7.64 (m, 3H), 7.62 (dd, J= 2.2, 0.5 Hz, 1H), 7.59 (d, J = 4.8 Hz, 1H), 6.37 (tt, J = 53.7, 3.1Hz, 1H), 4.77 (s, 2H), 4.10 (bs, 4H), 3.97-3.82 (m, 2H), 3.72- 3.50 (m,4H), 2.07-1.94 (m, 4H), 1.87 (s, 3H) 1410

MS (ESI) m/z = 791.4 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 6 12.44 (s,1H), 10.60-10.50 (b, 1H), 8.80 (s, 1H), 8.80 (d, J = 4.8 Hz, 1H), 8.78(s, 1H), 7.77 (dd, J = 8.3, 0.5 Hz, 1H), 7.70 (dd, J = 8.3, 2.1 Hz, 1H),7.67 (dd, J = 2.1, 0.5 Hz, 1H), 7.62 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H),4.27-3.90 (m, 6H), 3.79-3.56 (m, 4H expected; partially obscured bywater peak), 3.55 (s, 3H expected; partially obscured by water peak),2.12-1.95 (m, 4H), 2.00 (s, 3H), 1.73 (t, J = 19 Hz, 3H) 1411

MS (ESI) m/z = 833.3 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) 6 12.65 (bs,1H), 10.59 (bs, 1H), 8.78 (d, J = 4.8 Hz, 1H), 8.75 (s, 1H), 8.71 (s,1H), 7.74 (dd, J = 8.3, 0.5 Hz, 1H), 7.67 (dd, J = 8.3, 2.1, 1H), 7.64(dd, J = 2.1, 0.5 Hz, 1H), 7.59 (d, J = 4.8 Hz, 1H), 5.24-5.15 (m, 1H),4.98-4.85 (m, 4H), 4.79 (s, 2H), 4.21-3.87 (m, 4H), 3.74-3.54 (m, 4H),2.10-1.91 (m, 4H), 1.92 (s, 3H), 1.70 (t, J = 19.3 Hz, 3H) 1412

MS (ESI) m/z = 854.4 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) d/ppm =13.13-13.93 (b, 1H), 10.65-10.49 (b, 1H), 9.26 (dd, J = 2.4, 0.8 Hz,1H), 8.89 (dd, J = 4.9, 1.6 Hz, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.61 (s,1H), 8.52 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 8.46 (s, 1H), 7.73 (dd, J =8.4, 0.4 Hz, 1H), 7.69 (ddd, J = 8.1, 3.3, 0.8 Hz, 1H), 7.66 (dd, J =8.4, 2.2 Hz, 1H), 7.62 (dd, J = 2.2, 0.4 Hz, 1H), 7.59 (d, J = 4.8 Hz,1H), 4.77 (s, 2H), 4.24-3.90 (m, 6H expected, overlapping with waterpeak), 3.71-3.51 (m, 4H), 2.08-1.93 (m, 4H), 1.87 (s, 3H), 1.70 (t, J =19.4 Hz, 3H) 1413

MS (ESI) m/z 702.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H),8.81-8.72 (m, 2H), 8.64 (s, 1H), 7.79-7.72 (m, 1H), 7.71 −7.64 (m, 2H),7.54 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.32-3.89 (m, 6H), 3.64 (m, 4H),2.07 (d, J = 1.6 Hz, 6H), 2.00 (s, 3H), 1.74 (t, J = 19.6 Hz, 3H) 1414

LCMS (ESI) m/z 702.5 [M + 1]+ 1415

MS (ESI) m/z 629.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J =22.2 Hz, 1H), 8.78 (m, 1H), 8.44 (d, J = 17.1 Hz, 1H), 8.11 (d, J = 57.3Hz, 1H), 7.57 (m, 1H), 7.48-7.40 (m, 2H), 7.34 (dd, J = 12.2, 9.0 Hz,1H), 4.39 (m, 2H), 4.26 (d, J = 5.4 Hz, 2H), 3.47-3.31 (m, 2H), 3.25(dd, J = 13.1, 9.7 Hz, 1H), 2.29 (m, 1H), 2.22-2.11 (m, 1H), 2.11-2.01(m, 1H), 1.99 (d, J = 2.0 Hz, 3H), 1.82 (d, J = 14.3 Hz, 1H), 1.46 (s,1H), 1.26 (s, 3H) 1418

MS (ESI) m/z 644.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H),8.71 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.40 (s, 1H), 7.39 (d, J =2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.1 Hz, 2H),4.31-4.22 (m, 4H), 3.62 (d, J = 12.1 Hz, 2H), 3.40 (t, J = 13.0 Hz, 2H),3.20 (q, J = 11.4 Hz, 2H), 2.90 (s, 3H), 2.70 (s, 3H), 2.53 (s, 3H),2.00 (s, 3H) 1419

MS (ESI) m/z 588.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H),8.63 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H),7.41 (s, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.33 (q, J = 1.6 Hz, 1H), 5.97(q, J = 1.9 Hz, 1H), 4.54-4.48 (m, 2H), 4.42 (t, J = 5.0 Hz, 2H), 4.28(t, J = 5.1 Hz, 2H), 2.67 (s, 3H), 1.99 (s, 3H) 1421

MS (ESI) m/z 619.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (bs, 1H),7.92 (bs, 1H), 7.52 (d, J = 5.2 Hz, 1H), 7.34-7.27 (m, 2H), 7.14 (bs,1H), 4.35 (bs, 2H), 4.26 (bs, 2H), 4.04-3.97 (m, 2H), 3.74-3.67 (m, 2H),2.34 (s, 3H), 1.82 (s, 3H), 1.78 (s, 3H) 1422

MS (ESI) m/z 676.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.23 (bs,1H), 8.82 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 8.45 (s, 1H), 7.59- 7.57(m, 1H), 7.45 (d, J = 4.80, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.35 (d, J =8.8 Hz, 1H), 4.38 (s, 2H), 4.20 (s, 2H), 3.65 (s, 4H), 2.67 (s, 4H),2.60-2.48 (m, 2H), 1.74 (s, 3H), 1.35 (J = 21.6 Hz, 6H) 1423

MS (ESI) m/z 660.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (bs,1H), 8.79 (s, 1H), 8.75 (d, J = 4.64 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J =8.12 Hz, 1H), 7.68 (m, 2H), 7.53 (d, J = 4.64 Hz, 1H), 6.34 (m, 1H),4.82 (s, 2H), 3.76- 2.66 (m, 10H), 2.09 (s, 1H) 1424

MS (ESI) m/z 662.41 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.70 (s, 1H), 8.42 (s, 1H), 7.61 (dd, J = 8.8 Hz, 2.8 Hz,1H), 7.47 (d, J = 4.4 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.37 (d, J =9.2 Hz, 1H), 4.96- 4.67 (m, 2H), 4.40-4.21 (m, 5H), 3.57-3.36 (m, 8H),1.84 (s, 3H), 1.37 (d, J = 6.0 Hz, 3H) 1425

MS (ESI) m/z 688.50 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz,1H), 8.67 (s, 1H), 8.44 (s, 1H), 7.60 (dd, J = 2.8, 8.8 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.37 (d, J = 8.8 Hz,1H), 4.58-4.48 (m, 1H), 4.44-4.41 (m, 2H), 4.39-4.36 (m, 2H), 3.56-3.53(m, 4H), 3.30-3.28 (m, 1H), 3.17-2.95 (m, 4H), 2.22-2.19 (m, 2H), 1.84(s, 3H), 1.14- 0.77 (m, 4H) 1427

MS (ESI) m/z 697.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H),8.82 (d, J = 4.4 Hz, 1H), 8.41 (s, 1H), 7.59 (dd, J = 8.8, 2.8 Hz, 1H),7.46 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz,1H), 4.39 (t, J = 4.4 Hz, 2H), 4.24 (t, J = 4.4 Hz, 2H), 3.81-3.75 (m,1H), 3.31 (bs, 3H), 2.45 (s, 3H), 2.32-2.23 (m, 1H), 2.11-1.93 (m, 3H),1.92-1.66 (m, 5H) 1428

MS (ESI) m/z 702.53 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.59 (s, 1H), 8.42 (s, 1H), 7.59 (dd, J = 2.4, 8.8 Hz, 1H),7.46 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H) 7.36 (d, J = 9.2 Hz,1H), 4.52 (s, 2H), 4.37-4.40 (m, 2H), 4.23-4.26 (m, 1H), 4.18-4.21 (m,2H), 3.03 (s, 3H), 2.94-2.97 (m, 2H), 2.66-2.72 (m, 2H), 1.71-1.75 (m,7H), 0.64-0.68 (m, 4H) 1426

MS (ESI) m/z 724.56 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H),7.49 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.35 (d, J = 9.2 Hz,1H), 4.74 (s, 1H), 4.63 (s, 1H), 4.39 (t, J = 4.4 Hz, 2H), 4.21 (t, J =4.4 Hz, 2H), 3.69 (bs, 4H), 2.88 (bs, 4H), 2.72 (bs, 4H), 1.7(s, 3H)1430

MS (ESI) m/z 720.50 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.59 (s, 1H), 8.44 (s, 1H), 7.60 (dd, J = 2.4, 6.4 Hz, 1H),7.49 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.8 Hz, 1H), 7.37 (d, J = 8.8 Hz,1H), 6.08 (t, J = 55.6 Hz, 1H), 4.38 (d, J = 4.4 Hz, 2H), 4.25 (bs, 1H),4.19 (bs, 2H), 3.08 (bs, 2H), 3.03 (s, 3H), 2.92 (bs, 2H), 1.77 (bs,7H), 0.48-0.78 (m, 4H) 1431

MS (ESI) m/z 722.55 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.61 (s, 1H), 8.39 (s, 1H) 7.61 (dd, J = 2.4, 9.2 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.42-7.35 (m, 2H), 6.52 (t, J = 52 Hz, 1H),4.62-4.56 (m, 1H), 4.39 (bs, 2H), 4.21 (bs, 2H,), 3.38-3.34 (m, 4H),3.09 (s, 3H), 2.32-2.26 (m, 2H), 2.12-2.09 (m, 2H), 1.76 (s, 3H), 1.44(s, 6H) 1429

MS (ESI) m/z 704.54 [M − F1]; 1H NMR (400 MHz, DMSO-d6) 613.2 (bs, 1H),9.11 (bs, 1H), 8.83 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 8.38 (s, 1H),7.60 (dd, J = 2.8, 8.8 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J =2.8 Hz, 1H) 7.36 (d, J = 8.8 Hz, 1H), 4.74-4.62 (d, J = 46.8 Hz, 2H),4.60-4.57 (m, 1H), 4.39 (bs, 2H), 4.21 (bs, 2H), 3.66-3.58 (m, 2H),3.30-3.24 (m, 2H), 3.09 (s, 3H), 2.26-2.20 (m, 2H), 2.11-2.08 (m, 2H),1.76 (s, 3H), 1.38 (s, 6H) 1433

MS (ESI) m/z 708.50 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.2 Hz, 1H), 8.65 (s, 1H), 8.41 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H),7.47-7.43 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 6.51 (t, J = 53.4 Hz, 1H),4.38 (s, 4H), 4.21 (s, 2H), 3.07 (bs, 5H), 2.52 (s, 2H), 2.17 (bs, 2H),2.02 (bs, 2H), 1.75 (s, 3H), 1.11 (t, J = 6.3 Hz, 3H) 1434

MS (ESI) m/z 667.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (bs,1H), 8.81 (d, J = 4.8 Hz, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 7.60 (dd, J =9.2, 2.8 Hz, 1H), 7.44 (dd, J = 15.6 Hz, 2H), 7.35 (d, J = 9.2 Hz, 1H),4.59 (s, 2H), 4.53 (s, 2H), 4.38 (bs, 4H), 4.24- 4.20 (m, 4H), 3.91-3.88 (m, 1H), 2.17 (bs, 2H), 2.01 (t, J = 9.6 Hz, 2H), 1.82 (s, 3H),1.78-1.71 (m, 2H) 1432

MS (ESI) m/z 708.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (dd, J =4.8 Hz, 2 Hz, 1H), 8.61 (d, J = 2 Hz, 1H), 8.40 (s, 1H), 7.61 (d, J =8.8 Hz, 1H), 7.46 (dd, J = 4.8 Hz, 2 Hz, 1H), 7.43 (d, J = 4.0 Hz, 1H),7.36 (d, J = 7.2 Hz, 1H), 4.99 (bs, 4H), 4.58 (bs, 1H), 4.39 (s, 2H),4.21 (s, 2H), 4.0 (bs, 2H), 3.70 (bs, 2H), 3.28 (bs, 1H), 3.09 (s, 3H),2.33-2.00 (m, 4H), 1.76 (s, 3H) 1436

MS (ESI) m/z 682.52 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.5 (bs, 1H),9.66 (bs, 1H), 8.80 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 8.47 (s, 1H),7.60 (dd, J = 9.2, 2.8 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.42 (d, J =2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 4.65-4.45 (m, 8H), 4.40-4.35 (m,2H), 4.25-4.15 (m, 2H), 2.91 (bs, 1H), 1.80 (s, 3H), 1.17 (s, 3H), 1.06(s, 3H), 0.85-0.55 (m, 2H) 1437

MS (ESI) m/z 667.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (bs,1H), 8.81 (d, J = 4.8 Hz, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 7.60 (dd, J =9.2, 2.8 Hz, 1H), 7.44 (dd, J = 15.6 Hz, 2H), 7.35 (d, J = 9.2 Hz, 1H),4.59 (s, 2H), 4.53 (s, 2H), 4.38 (bs, 4H), 4.24- 4.20 (m, 4H), 3.91-3.88 (m, 1H), 2.17 (bs, 2H), 2.01 (t, J = 9.6 Hz, 2H), 1.82 (s, 3H),1.78-1.71 (m, 2H) 1435

MS (ESI) m/z 718.48 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.61 (s, 1H), 8.47 (s, 1H), 7.60 (dd, J = 9.2, 2.8 Hz, 1H),7.46 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 4.78-4.59 (m, 4H), 4.40-4.30 (m, 6H), 4.23-4.18 (m, 2H), 3.35-3.15(m, 2H), 2.80-2.65 (m, 2H), 1.80 (s, 3H), 1.47 (s, 3H) 1439

MS (ESI) m/z 692.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 6.54 (t, J = 54.8 Hz, 1H), 4.38 (d, J = 4.8 Hz, 2H), 4.22 (d, J =4.8 Hz, 2H), 4.10 (d, J = 12 Hz, 1H), 3.93 (d, J = 12.4 Hz, 1H),3.41-3.32 (m, 2H), 3.16-3.13 (m, 3H), 2.02 (bs, 1H),1.76 (s, 3H),0.53-0.41 (m, 4H) 1440

MS (ESI) m/z 693.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H),8.84 (d, J = 4.8 Hz, 1H), 8.33 (s, 1H), 7.65-7.58 (m, 1H), 7.48 (d, J =4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.40(t, J = 62.4 Hz, 1H), 4.41 (s, 2H), 4.28 (d, J = 5.2 Hz, 2H), 3.51-3.05(m, 8H), 2.50 (bs, 2H), 1.82 (s, 3H), 1.77 (s, 1H) 1438

MS (ESI) m/z 710.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.67 (s, 1H), 8.46 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz,1H), 7.49 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.36 (d, J =8.8 Hz, 1H), 4.39 (d, J = 4.8 Hz, 2H), 4.29 (bs, 2H), 3.96 (dd, J = 14,5.2 Hz, 1H), 3.87 (bs, 2H), 3.71 (bs, 1H), 3.59 (t, J = 9.2 Hz, 1H),3.27 (bs, 1H), 2.90 (d, J = 12.8 Hz, 1H), 2.26 (bs, 1H), 1.76 (s, 3H),0.58 (d, J = 6.4 Hz, 2H), 0.46 (s, 2H) 1443

MS (ESI) m/z 656.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H),8.75 (d, J = 4.8, 2H), 8.65 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.68 (d,J = 6.8 Hz, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.47 (d, J = 44Hz, 2H), 3.66 (bs, 4H), 2.96 (bs, 1H), 2.74 (s, 3H), 2.07-2.08 (m, 4H),1.23 (s, 3H) 1444

MS (ESI) m/z 650.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.29 (bs, 1H),8.83 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.76 (d, J = 8.4Hz, 1H), 7.70-7.65 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.46(bs, 2H), 3.53 (bs, 6H), 2.14 (s, 3H), 1.39 (s, 3H), 1.20 (bs, 2H), 0.83(bs, 2H) 1441

MS (ESI) m/z 728.40 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.59 (s, 1H), 8.44 (s, 1H), 7.60-7.58 (dd, J = 2.4, 8.8 Hz,1H), 7.48 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.36 (d, J =8.8 Hz, 1H), 4.38 (bs, 2H), 4.25-4.19 (m, 3H), 3.35-3.30 (m, 2H),3.07(s, 5H), 2.66-2.59 (m, 2H), 1.92 (d, J = 9.2 Hz, 2H), 1.78-1.72 (m,5H) 1446

MS (ESI) m/z 682.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.66 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.70-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.56-4.41 (m,2H), 3.77-3.06 (m, 8H), 2.23 (s, 3H), 1.23-0.72 (m, 6H) 1447

MS (ESI) m/z 664.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.99 (bs,1H), 9.00 (bs, 1H), 8.83 (bs, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s,1H), 7.75 (d, J = 8.4 Hz, 1H), 7.70-7.64 (m, 2H), 7.54 (d, J = 4.8 Hz,1H), 4.83 (s, 2H), 4.37 (bs, 2H), 3.85-3.40 (m, 6H), 2.90-2.80 (m, 1H),2.13 (s, 3H), 1.38 (s, 3H), 1.07 (s, 3H), 0.95-0.75 (m, 2H) 1445

MS (ESI) m/z 668.45 [M + 1]+; 1; H NMR (400 MHz, DMSO-d6) δ 8.79 (s,1H), 8.76 (d, J = 4.8 Hz, 1H), 8.66 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.69-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.60 (d, J =48.4 Hz, 2H), 3.80- 3.50 (m, 4H), 3.30-2.80 (m, 4H), 2.09 (s, 3H),1.20-0.80 (m, 4H) 1449

MS (ESI) m/z 688.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.69-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.72-4.54 (m,2H), 4.32 (bs, 2H), 3.14-2.67 (m, 8H), 2.10 (s, 3H), 1.48-1.45 (m, 3H)1450

MS (ESI) m/z 668.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.74 (bs, 1H),8.46 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.76 (d, J = 8.4Hz, 1H), 7.69-7.66 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 5.74 (d, J = 34.0Hz, 2H), 5.10 (s, 1H), 4.98 (s, 1H), 4.83 (s, 2H), 4.40 (d, J = 20.8 Hz,2H), 3.96 (bs, 2H), 3.65 (m, 2H), 3.54 (m, 2H), 3.29 (bs, 2H), 2.14 (s,3H) 1448

MS (ESI) m/z 674.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H),8.75 (d, J = 4.4 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H),7.69-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.91-4.83 (m, 6H), 4.12(bs, 1H), 3.79 (bs, 4H), 3.27 (bs, 4H), 2.10 (s, 3H) 1452

MS (ESI) m/z 670.50 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.76 (bs, 1H),8.84 (s, 1H), 8.76 (d, J = 4.4 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.70-7.66 (m, 2H), 7.54 (d, J = 4.8 Hz, 2H), 4.83 (s, 2H), 4.72(d, J = 46.8 Hz, 2H), 4.46 (d, J = 14.0 Hz, 2H), 3.85-3.50 (m, 4H),3.40-3.30 (m, 2H), 2.15 (s, 3H), 1.40 (s, 6H) 1453

MS (ESI) m/z 670.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.78 (bs, 1H),8.83 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.71-7.64 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.32(bs, 2H), 3.85- 3.30 (m, 8H), 2.13 (s, 3H), 1.50 (d, J = 21.2 Hz, 6H)1451

MS (ESI) m/z 664.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.70-7.66 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.36 (m, 2H),3.71-3.57 (m, 4H), 3.30-3.18 (m, 4H), 2.15 (s, 3H), 2.21 (s, 3H),0.60-0.51 (m, 4H) 1455

MS (ESI) m/z 688.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.66 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.69-7.67 (m, 2H), 7.54 (d, J = 4.8, 1H), 6.45- 6.14 (m, 1H), 4.82 (s,2H), 3.98-3.69 (m, 4H), 3.17 (m, 4H), 2.11 (s, 3H), 1.29 (s, 6H) 1456

MS (ESI) m/z 674.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.16 (bs,1H), 8.84 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J =8.4 Hz, 1H), 7.67 (t, J = 8.4 Hz, 2H), 7.53 (d, J = 4.8 Hz, 1H), 6.26(t, J = 56 Hz, 1H), 4.83 (s, 2H), 4.36 (bs, 2H), 3.73 (bs, 2H), 3.37(bs, 6H), 2.40 (bs, 2H), 2.13 (s, 3H) 1454

MS (ESI) m/z 684.48 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8 Hz, 1H),7.70-7.66 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.74-4.60 (m,2H), 4.47 (d, J = 13.6 Hz, 2H), 3.75 (d, J = 11.2 Hz, 2H), 3.60- 3.53(m, 2H), 3.31-3.28 (m, 2H), 2.21-2.15 (m, 5H) 1.42 (s, 6H) 1458

MS (ESI) m/z 706.49 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.96 (bs,1H), 8.84 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.76 (d, J =8.4 Hz, 1H), 7.69 (dd, J = 8.4, 2.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H),7.53 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H), 4.40-4.36 (m, 2H), 3.74-3.72 (m,2H), 3.29 (bs, 6H), 2.45-2.38 (m, 2H), 2.14 (s, 3H), 1.98-1.93 (m, 2H)1459

MS (ESI) m/z 642.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.69(dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.65 (s, 1H), 7.53 (d, J = 4.8 Hz, 1H),5.12-4.93 (m, 2H), 4.84 (s, 2H), 4.44 (dd, J = 42.4 Hz, 14.4 Hz, 1H),3.54-3.51 (m, 4H), 3.00 (s, 3H), 2.50-2.43 (m, 1H), 2.14 (s, 3H) 1457

MS (ESI) m/z 656.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H),8.75 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.70-7.65 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.65-4.50 (m,2H), 4.38 (d, J = 13.6 Hz, 2H), 3.46 (bs, 4H), 3.32 (bs, 4H), 2.19-2.06(m, 5H) 1461

MS (ESI) m/z 633.40 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (bs,1H), 9.51 (bs, 1H), 9.12 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 8.61 (s,1H), 7.76 (d, J = 9.1 Hz, 1H), 7.81-7.67 (m, 2H), 7.55 (d, J = 4.8 Hz,1H), 6.56 (s, 1H), 4.87 (s, 2H), 4.30-4.10 (m, 2H), 3.80 (bs, 1H), 3.01(bs, 4H), 2.19 (s, 3H), 1.10-0.84 (m, 4H) 1462

MS (ESI) m/z 639.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.07 (bs,1H), 10.26 (bs, 1H), 9.12 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.61 (s,1H), 7.76 (d, J = 8.8 Hz, 1H), 7.71-7.66 (m, 2H), 7.55 (d, J = 4.8 Hz,1H), 6.57 (s, 1H), 5.00-4.85 (m, 4H), 4.29-3.95 (m, 2H), 3.90-3.80 (m,2H), 3.60-3.45 (m, 2H), 3.10-2.90 (m, 2H), 2.18 (s, 3H) 1460

MS (ESI) m/z 708.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H),7.70-7.66 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H), 4.66-4.36 (m,5H), 3.91-3.78 (m, 4H), 2.95 (bs, 3H), 2.13 (s, 3H) 1464

MS (ESI) m/z 690.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.04 (bs,1H), 8.81-8.75 (m, 2H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.68 (d,J = 10.0 Hz, 1H), 7.53 (d, J = 4.4 Hz, 1H), 4.83 (s, 2H), 4.36-4.02 (m,4H), 3.69-3.59 (m, 4H), 3.36-2.9 (m, 4H), 2.11 (s, 3H) 1465

MS (ESI) m/z 680.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s,1H),8.76 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H),7.70-7.67 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.49-4.43 (m,2H), 3.76-3.46 (m, 8H), 3.26 (s, 3H), 2.49 (s, 1H), 2.12 (s, 3H), 1.25(bs, 2H), 0.97 (bs, 2H) 1463

MS (ESI) m/z 657.40 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.62 (s, 1H), 7.76 (d, J = 9.2 Hz, 1H),7.70-7.68 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 6.62-6.34 (m, 2H), 4.86 (s,2H), 3.41-3.24 (m, 4H), 3.15-2.95 (m, 2H), 2.87 (bs, 2H), 2.16 (s, 3H)1467

MS (ESI) m/z 686.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77-8.74 (m,2H), 8.64 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.69-7.67 (m, 2H), 7.54 (d,J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.57-4.55 (m, 4H), 4.24 (d, 2H),3.21-3.15 (m, 2H), 2.41 (s, 1H), 2.08-2.04 (m, 5H), 1.55 (s, 2H) 1468

MS (ESI) m/z 661.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.02 (bs,1H), 9.07 (s, 1H), 8.76 (s, 1H), 8.61 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H),7.69 (s, 2H), 7.53 (s, 1H), 4.87 (s, 2H), 3.90 (s, 2H), 3.50-3.30 (m,merged, 2H), 2.55 (s, 3H), 2.09 (s, 3H) 1466

MS (ESI) m/z 674.47 [M + 1]+; 1; H NMR (400 MHz, DMSO-d6) δ 8.80 (s,1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.69 (bs, 1H), 7.67 (s, 1H), 7.53 (d, J = 4.4 Hz, 1H), 6.31 (t, J = 53.2Hz, 1H), 4.82 (s, 2H), 3.79 (bs, 4H), 3.11 (bs, 4H), 2.64-2.59 (m, 1H),2.09 (s, 3H), 1.21 (bs, 3H) 1470

MS (ESI) m/z 674.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.74 (bs, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 7.61- 7.58 (dd, J= 2.4, 8.8 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H),7.38 (d, J = 8.8 Hz, 1H), 5.73 (d, J = 30.4 Hz, 2H), 5.09 (s, 1H), 4.98(s, 1H), 4.40 (d, J = 4.8 Hz, 2H), 4.31 (bs, 2H), 4.24 (d, J = 4.8 Hz,2H), 3.96 (bs, 2H), 3.63 (m, 2H), 3.32-3.18 (m, 4H), 1.84 (s, 3H) 1471

MS (ESI) m/z 724.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H),7.46 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 4.39 (s, 2H), 4.32-4.23 (m, 4H), 3.28-2.86 (m, 4H), 1.83 (s, 3H),1.30-1.21 (m, 4H) 1469

MS (ESI) m/z 704.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.9 Hz, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 7.55 (dd, J = 2.4, 8.8 Hz, 1H),7.50 (d, J = 4.9 Hz, 1H), 7.31 (d, J = 2.8 Hz, 2H), 4.46 (t, J = 4.9 Hz,2H), 4.34 (t, J = 4.9 Hz, 2H), 4.10 (bs, 4H), 3.72 (bs, 4H), 3.61 (s,2H), 2.11 (s, 3H), 1.99-1.80 (m, 4H), 1.03 (t, J = 7.4 Hz, 6H) 1473

MS (ESI) m/z 698.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.69 (bs, 1H), 8.45 (s, 1H), 7.59 (dd, J = 2.4, 9.2 Hz,1H), 7.45 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J =9.2 Hz, 1H), 4.39 (s, 2H), 4.22 (s, 4H), 3.54 (bs, 6H), 1.98-1.64 (m,2H), 1.18 (d, J = 7.2 Hz, 2H), 1.10-1.05 (m, 12H) 1474

MS (ESI) m/z 700.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =5.2 Hz, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 7.59-7.57 (dd, J = 2.4, 10.8Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.35 (d, J= 9.2 Hz, 1H), 4.36 (s, 2H), 4.19 (s, 2H), 3.65 (m, 4H), 4.44- 3.38 (m,2H), 2.87 (bs, 4H), 1.77 (s, 3H) 1472

MS (ESI) m/z 726.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.66 (bs, 1H), 8.45 (s, 1H), 7.59 (dd, J = 2.4, 9.2 Hz,1H), 7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J =9.2 Hz, 1H), 4.38 (s, 2H), 4.21 (s, 2H), 3.75 (bs, 8H), 2.71 (s, 2H),1.76 (s, 3H), 1.15 (s, 6H) 1476

MS (ESI) m/z 710.49 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.90 (bs, 1H),8.81 (d, J = 5.2 Hz, 1H), 8.61 (s, H), 8.47 (s, 1H), 7.60 (dd, J = 8.8,2.4 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.36(d, J = 8.8 Hz, 1H), 4.63 (s, 2H), 4.59-4.47 (m, 6H), 4.38 (t, J = 4.4Hz, 2H), 4.21 (d, J = 4.8 Hz, 2H), 2.70 (s, 1H), 1.81 (s, 3H), 1.09 (s,6H), 1.07 (s, 6H) 1477

MS (ESI) m/z 720.50 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.35 (bs,1H), 8.82 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.59 (dd, J =2.40, 8.8 Hz, 1H), 7.47 (d, J = 4.4 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H),7.36 (d, J = 8.8 Hz, 1H), 4.53 (bs, 1H), 4.39 (bs, 2H), 4.21 (bs, 2H),3.74 (bs, 1H), 3.58 (bs, 2H), 3.09 (bs, 9H), 2.10 (bs, 4H), 1.77 (s, 3H)1475

MS (ESI) m/z 704.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.8 Hz, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 7.59 (dd, J = 9.2, 2.8 Hz, 1H),7.46 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 9.2 Hz,1H), 4.53 (bs, 4H),4.45-4.35 (m, 2H), 4.25-4.15 (m, 2H), 3.60- 3.45 (m,1H), 3.20-2.70 (m, 4H), 2.60-2.40 (m, merged, 4H), 1.81 (s, 3H) 1479

MS (ESI) m/z 663.41 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.47(d, J = 4.4 Hz, 1H), 7.42 (bs, 1H), 7.36 (d, J = 8.8 Hz, 1H), 5.47 (d, J= 48.4 Hz, 1H), 4.93 (bs, 1H), 4.82 (bs, 1H), 4.39 (bs, 2H), 4.24 (bs,2H), 3.68 (bs, 4H), 3.37-3.27 (m, 4H), 2.29-2.10 (m, 1H), 2.01-1.98 (m,1H), 1.82-1.77 (m, 3H) 1480

MS (ESI) m/z 691.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H),8.84 (d, J = 4.8 Hz, 1H), 8.39 (s, 1H), 7.61-7.58 (dd, J = 2.8, 8.8 Hz,1H), 7.48-7.45 (dd, J = 10.8, 8.8 Hz, 2H), 7.37 (d, J = 9.2 Hz, 1H),6.46 (m, 1H), 4.40 (t, 2H), 4.25 (bs, 2H), 3.07-2.97 (m, 8H), 2.22 (m,2H), 2.06 (s, 3H), 1.79 (s, 3H) 1478

MS (ESI) m/z 692.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.8 Hz, 1H), 8.62 (s, 1H), 8.47 (s, 1H), 7.60 (dd, J = 9.2, 2.8 Hz, 1H),7.45 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 9.2 Hz,1H), 6.41 (t, J = 53.6 Hz, 1H), 4.38-4.37 (m, 2H), 4.21 (s, 2H), 3.91(bs, 6H), 3.17 (s, 4H), 3.03-2.81 (m, 2H), 1.79 (s, 3H) 1482

MS (ESI) m/z 628.33 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.04 (bs,1H), 9.07 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 7.77 (d, J =9.2 Hz, 1H), 7.69 (t, J = 3.2 Hz, 1H), 7.54 (d, J = 4.4 Hz, 1H), 6.33(s, 1H), 4.86 (s, 2H), 2.89-2.84 (m, 4H), 2.29-2.22 (m, 2H), 2.14 (s,3H) 1483

MS (ESI) m/z 753.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H),9.87 (bs, 1H), 8.90 (d, J = 4.8 Hz, 1H), 8.76 (s, H), 8.55 (s, 1H), 7.63(dd, J = 8.8, 2.4 Hz, 1H), 7.57 (d, J = 4.8 Hz, 1H), 7.44-7.37 (m, 2H),4.73 (d, J = 46.0 Hz, 2H), 4.50-4.35 (m, 4H), 4.23 (s, 2H), 3.80-3.50(m, 7H), 3.45-3.22 (m, 2H), 1.85 (s, 3H), 1.42 (s, 6H) 1481

MS (ESI) m/z 630.38 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H),8.57 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 7.77-7.75 (m, 1H), 7.69 (dd, J =2.0, 6.8 Hz, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.86 (s, 2H), 2.53 (s, 1H),2.17-2.15 (m, 3H), 2.08-2.06 (m, 2H), 2.01 (d, J = 5.6 Hz, 6H) 1485

MS (ESI) m/z 639.38 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H),8.82 (d, J = 4.4 Hz, 1H), 8.34 (s, 1H), 7.60 (dd, J = 9.2, 2.8 Hz, 1H),7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 9.2,1H), 6.36 (t, J = 49.2 Hz, 1H), 4.40 (t, J = 4.8 Hz, 2H), 4.27-4.26 (m,2H), 3.43 (bs, 4H), 2.73 (bs, 2H), 1.82 (s, 3H) 1486

MS (ESI) m/z 769.56 [M + 1]+ 1484

MS (ESI) m/z 679.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.85 (bs, 1H),8.96 (s, 1H), 8.82 (d, J = 4.8 Hz ,1H), 8.33 (s, 1H), 7.60 (dd, J = 2.4,8.8 Hz, 2H), 7.47-7.43 (m, 1H), 7.36 (d, J = 8.8 Hz ,1H), 6.66-6.39 (m,1H), 4.39 (t, J = 4.4 Hz ,2H), 4.25 (bs, 2H), 3.66-3.51 (m, 4H), 3.05(d, J = 5.6 Hz, 4H), 2.19 (bs, 1H), 1.80 (s, 6H), 1.63-1.60 (m, 2H) 1488

MS (ESI) m/z 719.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H),10.12 (bs, 1H), 8.89 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.79 (s, 1H),7.77 (d, J = 8.4 Hz, 1H), 7.72-7.69 (m, 1H), 7.66 (d, J = 1.6 Hz, 1H),7.62 (d, J = 4.8 Hz, 1H), 5.00-4.80 (m, 2H), 4.35 (bs, 2H), 3.82- 3.60(m, 4H), 3.55 (s, 3H), 3.50-3.22 (m, 4H), 2.03 (s, 3H) 1489

MS (ESI) m/z 698.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.68(d, J = 9.2 Hz, 2H), 7.53 (d, J = 4.4 Hz, 1H), 4.83 (s, 2H), 3.59 (bs,2H), 3.09 (bs, 8H), 5.19 (s, 5H), 1.82 (bs, 1H) 1487

MS (ESI) m/z 737.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.44 (bs,1H), 8.84-8.80 (m, 3H), 7.77 (d, J = 8.4 Hz, 1H), 7.71-7.66 (m, 2H),7.61 (d, J = 4.8 Hz, 1H), 6.32 (t, J = 52.0 Hz, 1H), 4.83 (s, 2H), 3.75(bs, 4H), 3.56 (bs, 3H), 2.95 (bs, 6H), 2.01 (s, 3H) 1491

MS (ESI) m/z 680.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) d 8.76 (d, J =4.8 Hz, 1H), 8.68 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.8 Hz, 1H), 7.68(d, J = 6.4 Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 3.82 (t, J= 6.8 Hz, 2H), 3.33-3.25 (m, 5H), 2.92 (t, J = 6.8 Hz, 2H), 2.45 (s,3H), 2.04 (s, 3H) 1492

MS (ESI) m/z 633.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H),8.73 (d, J = 4.8 Hz 1H), 8.59 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H),7.70-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 6.40 (t, J = 50.8 Hz, 1H),4.87 (s, 2H), 3.49 (bs, 4H), 3.12-2.77 (m, 5H), 2.17 (s, 3H) 1490

MS (ESI) m/z 700.41 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H),8.78 (s, 1H), 8.75 (d, J = 4.4 Hz, 1H), 8.64 (s, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.69 (d, J = 9.6 Hz, 2H), 7.54 (d, J = 4.8 Hz, 1H), 6.39 (bs,1H), 4.83 (s, 2H), 4.37-4.08 (m, 4H), 3.87 (bs, 4H), 3.26 (bs, 2H), 2.18(bs, 4H), 2.10 (s, 3H) 1494

MS (ESI) m/z 689.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 7.76 (d, J = 9.2 Hz, 1H),7.69-7.68 (m, 2H), 7.55 (d, J = 4.4 Hz, 1H), 4.82 (s, 2H), 4.30 (s, 1H),3.06-3.01 (m, 7H), 2.06 (s, 3H), 1.86-1.83 (m, 4H), 1.25 (dd, J = 8.0Hz, 5.6 Hz, 2H), 1.05 (dd, J = 7.2, 4.8 Hz, 2H) 1495

MS (ESI) m/z 638.41 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79-8.74 (m,2H), 8.65 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.55 (d,J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.54-4.53 (m, 1H), 3.58-3.55 (m, 2H),3.20 (bs, 2H), 3.01 (s, 3H), 2.83-2.82 (m, 3H), 2.10 (bs, 7H) 1493

MS (ESI) m/z 700.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H),7.70-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.43-3.90 (m,4H), 3.22-2.87 (m, 8H), 2.13 (s, 3H), 1.46 (s, 3H) 1497

MS (ESI) m/z 694.46 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.69 (d, J = 6.8 Hz, 1H), 7.76-7.43 (m, 1H), 7.68 (dd, J =2.0, 4.0 Hz, 1H), 7.54 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 3.73-3.70 (m,2H), 3.27 (bs, 5H), 2.68-2.64 (m, 2H), 2.41 (s, 3H), 2.05 (s, 3H), 1.90(t, J = 13.6 Hz, 2H) 1498

MS (ESI) m/z 595.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.11 (bs,1H), 9.73 (bs, 1H), 9.14 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.60 (s,1H), 7.76 (d, J = 9.2 Hz, 1H), 7.71-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz,1H), 7.39 (d, J = 15.2 Hz, 1H), 7.20-7.10 (m, 1H), 4.88 (s, 2H), 4.16-4.08 (m, 2H), 2.87 (s, 6H), 2.15 (s, 3H) 1496

MS (ESI) m/z 690.46 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.7 Hz 1H), 8.72 (s, 1H), 8.69 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H),7.66-7.64 (m, 2H), 7.53 (d, J = 4.6 Hz, 1H), 4.83 (s, 2H), 4.60-4.58 (m,1H), 3.18 (s, 3H), 3.10-3.00 (m, 1H), 2.27 (s, 3H), 1.60-1.57 (m, 1H),1.30-1.24 (m, 5H), 0.87-0.67 (m, 8H) 1500

MS (ESI) m/z 700.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J =4.8 Hz, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 7.75 (d, J = 8 Hz, 1H),7.68-7.66 (m, 2H), 7.51 (d, J = 4.8 Hz, 1H), 6.15 (tt, J = 4.0, 55.6 Hz,1H), 4.79 (s, 2H), 4.53 (t, J = 7.2 Hz, 2H), 2.89 (d, J = 11.2 Hz, 2H),2.77-2.67 (m, 4H), 2.21-2.16 (m, 4H), 2.03 (s, 3H), 1.81 (d, J = 11.6Hz, 2H) 1501

MS (ESI) m/z 783.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H),8.81 (d ,J = 5.6 Hz, 2H), 8.75 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H),7.71-7.68 (dd, J = 2.0, 10.4 Hz, 2H), 7.62 (d, J = 4.4 Hz, 1H), 4.82 (s,2H), 4.32 (bs, 1H), 3.55 (s, 3H), 3.31 (bs, 2H), 3.10 (bs, 5H), 2.51(bs, 2H), 1.97 (bs, 5H), 1.82-1.79 (m, 2H) 1499

MS (ESI) m/z 672.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.26 (bs,1H), 9.90 (bs, 1H), 8.89 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.69 (s,1H), 7.76 (d, J = 8.4 Hz, 1H), 7.71-7.66 (m, 2H), 7.55 (d, J = 4.8 Hz,1H), 6.48 (t, J = 53.2 Hz, 1H), 5.21-5.02 (m, 2H), 4.82 (s, 2H), 4.53(bs, 4H), 4.20-3.80 (m, 2H), 2.78-2.63 (m, 2H), 2.18 (s, 3H) 1503

MS (ESI) m/z 718.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.08 (bs,1H), 8.76-8.74 (m, 2H), 8.65 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H),7.69-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 6.79 (t, J = 74.8 Hz, 1H),4.82 (s, 2H), 4.56 (bs, 1H), 4.23 (s, 2H), 3.65 (bs, 2H), 3.46 (bs, 2H),3.26-3.19 (m, 2H), 3.11 (s, 3H), 2.26-2.08 (m, 2H), 2.04 (s, 5H) 1504

MS (ESI) m/z 744.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.8 Hz, 2H), 8.65 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 2.0Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 6.73 (t, J = 75 Hz, 1H), 4.82 (s,2H), 4.65 (bs, 1H), 4.21 (bs, 2H), 3.09 (s, 3H), 2.70-2.50 (m, 4H), 2.09(bs, 7H), 1.33 (bs, 2H), 1.12 (bs, 2H) 1502

MS (ESI) m/z 716.50 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.8 Hz, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H),7.68-7.66 (m, 2H), 7.50 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.28-4.22 (m,1H), 3.09 (s, 3H), 3.01 (d, J = 11.2 Hz, 2H), 2.75 (t, J = 14.4 Hz, 2H),2.38-2.32 (m, 2H), 2.05 (s, 3H), 2.01- 1.85 (m, 4H), 1.77 (d, J = 11.6Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H) 1506

MS (ESI) m/z 730.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76-8.74 (m,2H), 8.65 (s, 1H), 7.75 (d, J = 6.0 Hz, 1H), 7.70-7.67 (m, 2H), 7.55 (d,J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.65-4.60 (m, 1H), 3.91-3.78 (m, 2H),3.41-3.39 (m, 2H), 3.22 (s, 3H), 2.32-2.26 (m, 2H), 2.24- 2.08 (m, 5H),1.84-1.79 (m, 3H), 1.51 (s, 6H) 1507

MS (ESI) m/z 734.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 7.76 (d, J = 5.2 Hz, 1H),7.70-7.67 (m, 2H), 7.55 (d, J = 4.8 Hz, H), 4.81 (s, 2H), 4.30-4.06 (m,2H), 3.53-3.37 (m, 2H), 3.08 (s, 3H), 2.05 (s, 3H), 1.90-1.86 (m, 4H),1.33 (s, 6H) 1505

MS (ESI) m/z 671.41 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.68 (d, J = 1.6 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H),7.70-7.67 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 3H), 3.38-3.28 (m,4H), 3.11 (s, 9H), 2.02 (s, 3H), 1.97-1.91 (m, 2H), 1.89-1.83 (m, 2H)1509

MS (ESI) m/z 704.38 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.06 (bs,1H), 9.76 (bs, 1H), 8.84 (s,1H), 8.75 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H),7.75 (d, J = 8.4 Hz, 1H), 7.70-7.65 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H),6.71 (t, J = 75.6 Hz, 1H), 4.83 (s, 2H), 4.40-4.36 (m, 2H), 3.94 (t, J =6.0 Hz, 2H), 3.74-3.71 (m, 2H), 3.60- 3.20 (m, 6H), 2.14 (s, 3H),2.10-2.05 (m, 2H) 1510

MS (ESI) m/z 716.40 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.15 (bs,1H), 8.79 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.66 (s, 1H), 7.75 (d, J =9.1 Hz, 1H), 7.69-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 6.68 (t, J =75.9 Hz, 1H), 4.82 (s, 2H), 4.01 (bs, 2H), 3.40-2.80 (m, 8H), 2.08 (s,3H), 1.05-0.65 (m, 4H) 1508

MS (ESI) m/z, 684.48 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.69(d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (bs,4H), 4.68-4.62 (m, 2H), 3.60 (bs, 2H), 3.33 (bs, 2H), 3.11 (s, 3H), 2.24(bs, 2H), 2.13 (bs, 2H), 2.09 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H) 1512

MS (ESI) m/z 745.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H),10.01 (bs, 1H), 8.87 (d, J = 4.8 Hz, 1H ), 8.62 (s, 1H ), 8.60 (s, 1H ),7.61 (dd, J = 8.8, 4.8 Hz, 1H), 7.54 (d, J = 4.8 Hz, 1H), 7.43 (d, J =2.5 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 4.60 (s, 2H), 4.54 (s, 2H),4.44-4.37 (m, 4H), 4.28-4.16 (m, 4H), 4.00-3.80 (m, 1H), 3.49 (s, 3H),2.23-2.14 (m, 2H), 2.09-1.95 (m, 2H), 1.85-1.70 (m, 5H) 1513

MS (ESI) m/z 724.49 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H),7.46 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 9.2 Hz,1H), 6.79 (t, J = 75.2 Hz, 1H), 4.54-4.51 (m, 1H), 4.38 (d, J = 4.4 Hz,2H), 4.28 (d, J = 4.4 Hz, 4H), 3.67-3.63 (m, 2H), 3.45 (bs, 2H),3.25-3.22 (m, 2H), 3.09 (s, 3H), 2.21-2.15 (m, 2H), 2.08-2.05 (m, 2H),1.71 (s, 3H) 1511

MS (ESI) m/z 716.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.01 (bs,1H), 10.04 (bs, 1H), 8.84 (s, 1H), 8.75 (d, J = 4.8 Hz,1H), 8.64 (s,1H),7.75 (d, J = 8.4 Hz, 1H), 7.70-7.60 (m, 2H), 7.52 (d, J = 4.4 Hz,1H),6.71 (t, J = 75.2 Hz, 1H), 4.83 (s, 2H), 4.55-4.36 (m, 3H), 3.70- 3.40(m, 5H), 3.16 (bs, 2H), 2.77 (bs, 2H), 2.50-2.35 (m, 2H), 2.14 (s, 3H)1515

MS (ESI) m/z 744.51 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.60 (s, 1H), 7.85 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.48 (d, J= 4.8 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 6.57(t, J = 52 Hz, 1H), 4.38 (d, J = 4.8 Hz, 2H), 4.30-4.02 (m, 3H),3.30-2.89 (m, 9H), 1.99 (bs, 2H), 1.82 (bs, 2H), 1.74 (s, 3H) 1516

MS (ESI) m/z 753.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H),9.81 (bs, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.75 (s, 1H), 8.57 (s, 1H),7.59 (dd, J = 2.8, 9.2 Hz, 1H), 7.56 (d, J = 4.8 Hz, 1H), 7.40 (d, J =8.4 Hz, 2H), 2.26 (s, 2H), 4.23 (s, 4H), 3.80 (bs, 6H), 3.61 (s, 3 H),3.42 (bs, 2H), 1.81 (s, 3H), 1.53-1.48 (m, 6H) 1514

MS (ESI) m/z 740.49 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.59 (s, 1H), 8.43 (s, 1H), 7.60 (dd, J = 9.2, 2.8 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz,1H), 4.38-4.37 (m, 2H), 4.26 (bs, 2H), 4.19 (s,2H), 3.36 (bs, 2H), 3.05(s, 3H), 1.83 (bs, 4H), 1.73 (s, 4H), 1.33 (s, 6H) 1519

MS (ESI) m/z 680.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.08 (bs,1H), 8.75 (d, J = 4.8 Hz, 2H), 8.64 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.69 (d, J = 2 Hz, 2H), 7.5 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.57 (bs,2H), 4.34 (bs, 2H), 3.23 (d, J = 11.6 Hz, 2H), 3.19 (s, 1H), 3.11 (s,3H), 2.31 (m, 2H), 2.21 (s, 3H), 2.10-2.03 (m, 5H) 1520

MS (ESI) m/z 720.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.09 (bs,1H), 8.77-8.75 (m, 2H), 8.65 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.68 (d,J = 9.2 Hz, 2H), 7.55 (d, J = 4.4 Hz, 1H), 4.83 (s, 2H), 4.55 (bs, 1H),3.70 (bs, 2H), 3.24 (bs, 4H), 3.11 (bs, 3H), 2.89 (bs, 2H), 2.15-2.11(m, 7H) 1518

MS (ESI) m/z 702.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.8 Hz, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.69(s, 1H), 7.67 (s, 1H), 7.55 (d, J = 4.8 Hz, 1H), 6.53 (t, J = 50.0 Hz,1H), 4.82 (bs, 2H), 4.57 (d, J = 2.4 Hz, 1H), 3.58 (bs, 2H), 3.36 (bs,2H), 3.16 (s, 3H), 2.98 (bs, 1H), 2.24 (bs, 2H), 2.08 (bs, 5H), 1.35 (s,3H) 1522

MS (ESI) m/z 714.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.71 (s, 1H), 7.66 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.68(t, J = 2.8 Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 6.08 (t, J = 56.4 Hz,1H), 4.81 (s, 2H), 4.09 (bs, 1H), 3.05 (bs, 5H), 2.92 (bs, 2H), 2.05 (s,3H), 1.79-1.73 (m, 4H), 0.85-0.78 (m, 4H) 1523

MS (ESI) m/z 680.48 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =6.4 Hz, 2H), 8.64 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.70-7.67 (m, 2H),7.55 (d, J = 4.4 Hz, 1H), 4.82 (s, 2H), 4.80-4.76 (m, 4H), 4.58 (bs,1H), 4.37 (bs, 1H), 3.55 (d, J = 8.8 Hz, 2H), 3.12 (bs, 5H), 2.15- 2.10(m, 5H), remainder of protons are merged in moisture peak 1521

MS (ESI) m/z 784.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76-8.75 (m,2H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.70-7.67 (m, 2H), 7.54 (d,J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.56 (dt, J = 47.2, 5.6 Hz, 2H),4.59-4.57 (m, 1H), 3.68-3.55 (m, 2H), 3.21-3.19 (m, 4H), 3.11 (s, 3H),2.21-2.05 (m, 9H) 1525

MS (ESI) m/z 648.39 [M + 1]; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H),8.76 (d, J = 4.4 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.70-7.67 (m, 1H), 7.55 (d, J = 4.8 Hz, 1H), 5.13 (bs, 1H), 4.81-4.67(m, 6H), 3.97 (bs, 2H), 2.77 (bs, 2H), 2.10 (s, 3H), 0.85 (bs, 4H) 1526

MS (ESI) m/z 704.41 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.16 (bs,1H), 8.79 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J =8.3 Hz, 1H), 7.69-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H),3.73 bs, 4H), 3.00 (bs, 4H), 2.70-2.50 (m, merged, 1H), 2.20-2.07 (m,1H), 2.08 (s, 3H), 1.03-1.08 (m, 2H) 1524

MS (ESI) m/z 678.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.06 (bs,1H), 8.75.-8.74 (m, 2H), 8.65 (s, 1H), 7.75 (d, J = 8.4 Hz ,1H), 7.68(d, J = 8.8 Hz ,2H), 7.54 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.64 (t, J= 8.4 Hz, 1H), 3.49 (s, 4H), 3.10 (s, 3H), 2.21-2.08 (m, 7H), 1.39 (s,3H), 1.14 (bs, 2H), 0.81 (bs, 2H) 1528

MS (ESI) m/z 625.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H),7.70-7.65 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.60-4.45 (m,1H), 4.05-3.95 (m, 2H), 3.65-3.40 (m, 2H), 3.11 (s, 3H), 2.06 (s, 3H),2.00-1.85 (m, 2H), 1.78 (d, J = 10.8 Hz, 2H) 1529

MS (ESI) m/z 696.48 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.00 (bs, 1H),8.76-8.74 (m, 2H), 8.65 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70-7.67 (m,2H), 7.75 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.72-4.66 (m, 2H), 3.65(bs, 4H), 3.09 (s, 3H), 2.71 (s, 1H), 2.12-2.08 (m, 7H), 1.35 (bs, 2H),1.16 (bs, 2H) 1527

MS (ESI) m/z 664.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.05 (bs, 1H),8.79 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.0Hz, 1H), 7.71-7.65 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.39(d, J = 12.4 Hz, 2H), 3.19 (t, J = 12.0 Hz, 2H), 2.95-2.90 (m, 5H),2.32-2.28 (m, 2H), 2.10 (s, 3H), 2.00-1.80 (m, 2H), 1.02-0.91 (m, 2H),0.90-0.81 (m, 2H) 1531

MS (ESI) m/z 714.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.06 (bs,1H), 10.53 (bs, 1H), 8.77-8.70 (m, 2H), 8.65 (s, 1H), 7.75 (d, J = 4.4Hz, 1H), 7.69-7.67 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 6.49 (t, J = 56.4Hz, 1H), 4.82 (s, 2H), 4.57 (bs, 2H), 3.80-3.48 (m, 3H), 3.40- 3.20 (m,2H), 3.16 (s, 4H), 3.01-2.70 (m, 2H), 2.02-2.15 (m, 2H), 2.06 (s, 3H),1.80-1.65 (m, 2H) 1532

MS (ESI) m/z 670.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.05 (bs,1H), 8.76-8.70 (m, 2H), 8.65 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H),7.70-7.68 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.96- 4.68 (m, 4H),4.01-3.95 (m, 1H), 3.65- 3.28 (m, 3H), 3.22 (s, 3H), 2.82 (s, 3H), 2.80-2.55 (m, 4H), 2.08 (s, 3H) 1530

MS (ESI) m/z 732.40 [M + 1]+; 1H NMR (400 MHz, DMSO- d6) δ 8.76 (d, J =4.8, 1H), 8.70 (s, 1H), 8.65 (s, 1H), 7.79-7.73 (m, 1H), 7.71- 7.65 (m,2H), 7.55 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.32-4.20 (m, 1H),3.12-3.10 (m, 5H), 2.81 (t, J = 11.2 Hz, 2H), 2.05 (s, 3H), 1.85-1.65(m, 4H), 1.06-0.90 (m, 4H) 1534

MS (ESI) m/z 597.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H),8.79-8.75 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.71-7.66 (m, 2H), 7.54 (d,J = 4.4 Hz, 1H), 5.00-4.97 (m, 1H), 4.88 (d, J = 18.4 Hz, 1H), 4.77-4.73(m, 2H), 4.44 (bs, 1H), 3.89 (d, J = 12.0 Hz, 1H), 3.64 (d, J = 12.0 Hz,1H), 3.57 (s, 3H), 2.13 (s, 3H) 1535

MS (ESI) m/z 702.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.4 Hz, 2H), 8.66 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.70-7.68 (m, 2H),7.55 (d, J = 4.8 Hz, 1H), 6.51 (bs, 1H), 4.82 (s, 2H), 4.35 (bs, 1H),3.66-3.51 (m, 6H), 3.06-2.97 (m, 2H), 2.16-2.02 (m, 7H), 1.13 (t, J =6.8 Hz, 3H) 1533

MS (ESI) m/z 698.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (bs, 1H),8.76-8.75 (m, 2H), 8.65 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.70-7.68 (m,2H), 7.55 (d, J = 8.8 Hz, 1H), 4.95-4.82 (m, 4H), 4.35-4.25 (m, 1H),3.60-3.40 (m, 3H), 3.12 (s, 3H), 2.95-2.90 (m, 3H), 2.13- 1.72(m, 11H)1537

MS (ESI) m/z 768.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J =5.2 Hz, 1H), 8.70 (s, 1H), 8.63 (s, 1H), 7.83 (bs, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.70-7.69 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 6.74-6.60 (m, 1H),6.48 (bs, 1H), 4.81 (s, 2H), 4.5-4.25 (m, 2H), 4.15-4.05 (bs, 2H), 3.90(s, 3H), 3.45-3.3 (bs, 2H), 3.09 (s, 3H), 2.2-2.13 (bs, 2H), 2.06 (s,3H), 2.05-1.9 (bs, 2H) 1538

MS (ESI) m/z 811.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H),8.85 (d, J = 4.8 Hz 1H), 8.70 (s, 2H), 8.69 (s, 1H), 7.78- 7.69 (m, 3H),7.63 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.32 (t, J = 11.6 Hz, 1H),3.94-3.87 (m, 2H), 3.31 (bs, 2H), 3.10-3.07 (m, 5H), 2.59 (m, 1H), 1.96(d, J = 9.3 Hz, 2H), 1.90-1.77 (m, 5H), 1.44 (s, 6H) 1536

MS (ESI) m/z 768.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 7.90 (bs, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.55 (d, J = 4.8 Hz,1H), 6.61 (bs, 1H), 4.82 (s, 2H), 4.53-4.24 (m, 5H), 3.92 (s, 3H), 3.53(m, 2H), 3.09 (s, 5H), 2.00 (s, 5H) 1540

MS (ESI) m/z 688.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80-8.74 (m,2H), 8.65 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.70-7.66 (m, 1H), 7.55 (d,J = 4.8 Hz, 1H), 6.47 (t, J = 58.0 Hz, 1H), 4.83 (s, 2H), 4.68 (bs, 1H),3.70-3.40 (m, 4H), 3.16 (s, 3H), 3.08-2.75 (m, 2H), 2.08 (s, 3H),2.05-1.75 (m, 4H) 1541

MS (ESI) m/z 701.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (bs, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.69-8.66 (m, 2H), 7.76 (d, J = 8.8 Hz, 1H),7.68 (t, J = 3.6 Hz, 2H), 7.55 (d, J = 4.4 Hz, 1H), 6.59 (bs, 1H), 4.81(s, 2H), 3.72 (d, J = 6.0 Hz, 2H), 3.40 (bs, 4H), 3.33 (s, 3H),3.11-2.99 (m, 2H), 2.06 (s, 3H), 1.79 (bs, 4H), 1.47 (bs, 1H) 1539

MS (ESI) m/z 833.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.88 (bs,1H), 8.84-8.83 (m, 2H), 8.73 (s, 1H), 7.77 (d, J = 4.4 Hz, 1H),7.76-7.69 (m, 2H), 7.63 (d, J = 4.8 Hz, 1H), 6.73-6.46 (tt, J = 54.4,4.4 Hz, 1H), 4.82 (s, 2H), 4.49 (dt, J = 14.8, 4.0 Hz, 2H), 4.36-4.30(m, 1H), 3.36 (bs, 2H), 3.10 (s, 5H), 2.66-2.63 (m, 2H), 2.05-1.77 (m,7H) 1543

MS (ESI) m/z 707.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.35 (bs,1H), 8.38 (d, J = 4.8 Hz, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.61 (dd, J =2.4, 8.8 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H),7.37 (d, J = 8.8 Hz, 1H), 5.46-5.45 (m, 1H), 4.39 (bs, 2H), 4.24 (bs,2H), 3.92 (m, 1H), 3.60-3.58 (m, 2H), 3.08- 3.05 (m, 8H), 2.14-1.90 (m,2H), 1.79-1.77 (m, 3H) 1544

MS (ESI) m/z 714.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 2H), 8.64 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.69 (t, J = 8.8Hz, 2H), 7.54 (d, J = 4.8 Hz, 1H), 6.49 (bs, 1H), 4.82 (s, 2H), 4.49 (s,1H), 3.75 (bs, 8H), 2.97 (s, 2H), 2.08 (bs, 5H), 1.81 (s, 1H), 1.68 (d,J = 12.8 Hz, 2H) 1542

MS (ESI) m/z 674.40 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H),8.81 (d, J = 4.8 Hz, 1H), 8.73 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H),7.72-7.69 (m, 2H), 7.57 (d, J = 4.4 Hz, 1H), 6.42-6.15 (m, 1H),4.90-4.80 (m, 3H), 4.51-4.46 (m, 1H), 3.87-3.84 (m, 2H), 3.68-3.61 (m,3H), 3.58-3.37 (m, 2H), 3.25-3.17 (m, 2H), 2.87 (bs, 2H), 2.17 (s, 3H)1546

MS (ESI) m/z 811.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H),8.82 (d, J = 4.8 Hz, 1H), 8.74 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.8 Hz,1H), 7.70 (d, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.61 (d, J = 4.8 Hz, 1H),4.82 (s, 2H), 4.29 (t, J = 23.2 Hz, 1H), 3.22 (q, J = 10.0 Hz, 2H), 3.09(s, 3H), 3.04 (d, J = 19.2 Hz, 10H), 1.92 (d, J = 8.0 Hz, 5H), 1.78 (d,J = 9.6 Hz, 2H) 1547

MS (ESI) m/z 809.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H),8.79 (t, J = 8.0 Hz, 2H), 8.73 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.70(d, J = 2 Hz, 2H), 7.60 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.31 (t, J =21.2 Hz, 1H), 3.29-3.22 (m, 4H), 3.10 (bs, 5H), 2.50 (s, 1H), 1.94 (d, J= 11.7 Hz, 5H), 1.78 (s, 2H), 1.29 (d, J = 3.8 Hz, 2H), 1.26-1.14 (m,2H) 1545

MS (ESI) m/z 714.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 at 353.1 K) 68.15(s, 1H), 8.77 (d, J = 4.8 Hz, 1H), 8.68 (s, 1H), 7.75 (d, J = 8.4 Hz,1H), 7.67-7.64 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.86-4.80 (m, 2H),4.08-4.05 (m, 1H), 3.09 (s, 3H), 2.98 (m, 3H), 2.18 (s, 3H), 2.06- 2.01(m, 1H), 1.67 (t, J = 18.4 Hz, 3H), 1.38- 1.26 (m, 4H) 1549

MS (ESI) m/z 859.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (bs,1H), 8.93 (d, J = 4.8 Hz, 1H), 8.56 (s, 1H), 8.25 (s, 1H), 8.17 (d, J =7.6 Hz, 1H), 7.77-7.55 (m, 1H), 7.70-7.63 (m, 4H), 7.55-7.51 (m, 1H),7.45 (d, J = 7.6 Hz, 1H) 4.82 (s, 2H), 4.29 (bs, 1H), 3.31 (bs, 2H),3.08 (bs, 5H), 2.67 (s, 3H), 2.63-2.58 (m, 2H), 1.94-1.88 (m, 2H). 1.83(s, 3H), 1.79-1.76 (m, 2H) 1550

MS (ESI) m/z 881.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.28 (bs,1H), 8.94 (d, J = 5.2 Hz, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 8.24- 8.19(m, 1H), 7.77-7.75 (m, 1H), 7.70-7.68 (m, 2H), 7.66 (d, J = 4.8 Hz, 1H),7.61-7.56 (m, 1H), 7.48-7.40 (m, 1H), 4.80 (s, 2H), 4.37-4.26 (m, 1H),3.37 (bs, 2H), 3.12-3.10 (m, 2H), 3.07 (s, 3H), 2.66-2.63 (m, 2H),1.99-1.88 (m, 2H), 1.85-1.74 (m, 5H) 1548

MS (ESI) m/z 845.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.09 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 8.15 (d, J =7.2 Hz, 2H), 7.78-7.74 (m, 2H), 7.69-7.66 (m, 4H), 7.61 (d, J = 4.8 Hz,1H), 4.80 (s, 2H), 4.31 (bs, 1H), 3.28 (bs, 2H), 3.09-3.06 (m, 5H),2.58-2.50 (m, 2H), 1.94 (d, J = 11.2 Hz, 2H), 1.87 (s, 3H), 1.79 (d,10.4 Hz, 2H) 1553

MS (ESI) m/z 730.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H),8.56 (s, 1H), 7.60-7.73 (m, 1H), 7.67-7.66 (m, 2H), 7.51 (d, J = 4.8 Hz,1H), 6.14-5.56 (m, 1H), 4.82 (s, 2H), 4.59-4.55 (m, 2H), 4.48 (t, J =6.4 Hz, 2H), 4.34-4.31 (m, 2H), 4.26-4.21 (m, 1H), 3.14-3.03 (m, 4H),2.87 (t, J = 12.4 Hz, 1H), 2.07 (s, 3H), 1.76 (d, J = 12.0 Hz, 2H),1.56-1.48 (m, 2H) 1554

MS (ESI) m/z 757.34 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H),8.79 (d, J = 4.8 7.71 (d, J = 2.0 Hz, 1H), 7.68 (bs, 1H), 7.58 (d, J =4.4 Hz, 1H), 6.29 (t, J = 61.2 Hz, 1H), 4.86 (s, 2H), 4.44 (bs, 2H),4.04 (bs, 4H), 3.25 (bs, 2H), 2.16 (bs, 4H), 2.10 (bs, 3H) 1551

MS (ESI) m/z 859.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (bs,1H), 8.93 (d, J = 4.8 Hz, 1H), 8.56 (s, 1H), 8.25 (s, 1H), 8.17 (d, J =7.6 Hz, 1H), 7.77-7.55 (m, 1H), 7.70-7.63 (m, 4H), 7.55-7.51 (m, 1H),7.45 (d, J = 7.6 Hz, 1H) 4.82 (s, 2H), 4.29 (bs, 1H), 3.31 (bs, 2H),3.08 (bs, 5H), 2.67 (s, 3H), 2.63-2.58 (m, 2H), 1.94-1.88 (m, 2H). 1.83(s, 3H), 1.79-1.76 (m, 2H) 1556

MS (ESI) m/z 700.34 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H),8.77-8.74 (m 2H), 8.65 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.70-7.66 (dd,J = 2.0, 10.4 Hz, 2H), 7.55 (d, J = 4.4 Hz, 1H), 6.54 (bs, 1H), 4.82 (s,2H), 4.42 (s, 1H), 4.19 (bs, 1H), 3.86-3.59 (bs, 4H), 3.16- 2.74 (bs,4H), 2.11 (s, 5H), 1.97-1.78 (bs, 2H) 1557

MS (ESI) m/z 702.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.00 (bs,1H), 10.03 (bs, Hz, 1H), 8.59 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), CI1H), 8.80-8.68 (m, 3H), 7.74-7.63 (m, 3H), 7.59 (d, J = 5.2 Hz, 1H),6.53 (t, J = 54.4 Hz, 1H), 5.90-5.40 (m, 1H), 4.48 (bs, 1H), 3.81-3.41(m, 4H), 3.38-3.10 (m, 2H), 3.09 (s, 3H), 2.40-1.95 (m, 7H), 1.47 (t, J= 6.8 Hz, 3H) 1555

MS (ESI) m/z 764.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.13 (bs,1H), 8.77 (s, 1H), 8.75 (d, J = 7.2 Hz, 1H), 8.65 (s, 1H), 7.76 (s, 1H),7.70 (d, J = 2.0 Hz, 2H), 7.67-7.54 (m, 6H), 4.82 (s, 2H), 4.56-4.22 (m,5H), 3.01 (s, 5H), 2.97-2.87 (m, 2H), 2.09 (s, 5H) 1559

MS (ESI) m/z 695.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.22 (bs, 1H),8.78 (d, J = 4.7 Hz, 1H), 8.65 (s, 1H), 8.00-7.99 (m, 2H), 7.77 (d, J =9.0 Hz, 1H), 7.70-7.66 (m, 4H), 7.56 (d, J = 4.7 Hz, 1H), 6.43 (t, J =53.4 Hz, 1H), 4.90 (s, 2H), 4.23 (bs, 2H), 3.41 (bs, 2H), 2.66 (bs, 3H),2.19 (s, 3H) 1560

MS (ESI) m/z 703.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H),9.44 (bs, 1H), 8.73 (s, 1H), 8.68 (d, J = 4.8 Hz, 1H), 8.48 (s, 1H),7.74-7.72 (m, 1H), 7.66-7.64 (m, 2H), 7.48 (d, J = 4.8 Hz, 1H), 6.45 (b,1H), 4.80 (s, 2H), 4.49 (bs, 1H), 3.35 (s, 4H), 3.08 (s, 3H), 2.50- 2.47(m, 2H), 2.08 (bs, 2H), 1.99 (s, 5H) 1558

MS (ESI) m/z 707.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H),8.79 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H),7.70-7.68 (m, 2H), 7.56 (d, J = 4.8 Hz, 1H), 7.49-7.44 (m, 2H), 7.36(bs, 1H), 6.42 (tt, J = 52.4, 7.4 Hz, 1H), 4.90 (s, 2H), 4.38 (bs, 2H),3.48 (bs, 2H), 3.24 (bs, 2H), 2.86 (bs, 2H), 2.16 (s, 3H) 1562

MS (ESI) m/z 722.38 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (bs, 1H),8.81 (d, J = 4.8 Hz, 1H), 8.46 (s, 1H), 7.61-7.58 (m, 1H), 7.46 (d, J =4.8 Hz, 1H), 7.41-7.36 (m, 2H), 4.50 (m, 1H), 4.41 (bs, 2H), 4.21 (bs,2H), 3.65- 3.37 (m, 4H), 3.06 (s, 3H), 2.62 (s, 3H), 2.25 (m, 2H), 2.00(m, 2H), 1.79-1.69 (m, 8H) 1563

MS (ESI) m/z 722.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H),8.41 (bs, 1H), 7.59 (dd, J = 2.4, 8.8 Hz, 1H), 7.42-7.40 (m, 2H), 7.36(d, J = 9.2 Hz, 1H), 4.53 (bs, 1H), 4.38 (bs, 2H), 4.21 (bs, 2H), 3.84(bs, 4H), 3.08 (s, 3H), 3.54 (bs, 2H), 2.70 (s, 3H)), 1.99 (bs, 2H),1.82 (bs, 5H), 1.76 (bs, 3H) 1561

MS (ESI) m/z 757.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H),8.81-8.78 (m, 3H), 7.77 (d, J = 8.4, 1H), 7.72-7.67 (m, 2H), 7.62 (d, J= 4.8 Hz, 1H), 4.83 (s, 2H), 4.78 (t, J = 6.8 Hz, 4H), 4.60 (bs, 1H),4.36 (bs, 1H), 3.58 (bs, 2H), 3.53 (s, 3H), 3.12 (s, 3H), 3.05 (d, J =14.0 Hz, 2H), 2.14 (bs, 4H), 1.99 (s, 3H) 1565

MS (ESI) m/z 708.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H),7.70-7.66 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H), 4.66-4.36 (m,5H), 3.91-3.78 (m, 4H), 2.95 (bs, 3H), 2.13 (s, 3H) 1566

MS (ESI) m/z 828.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H),8.90 (d, J = 4.8 Hz, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.65 (s, 1H), 8.60(s, 1H), 8.27-8.18 (m, 2H), 7.77-7.53 (m, 4H), 7.49 (d, J = 5.6 Hz, 1H),6.66-6.29 (m, 1H), 4.82 (s, 2H), 4.60-4.45 (m, 1H), 3.50-3.15 (m, 6H),3.09 (s, 3H), 2.30-1.80 (m, 7H) 1564

MS (ESI) m/z 668.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H),7.67-7.70 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 5.45 (d, J = 56.8 Hz, 1H),4.83 (s, 2H), 4.54- 4.29 (m, 5H), 3.52 (bs, 2H), 3.15-3.09 (m, 2H),2.19-2.09 (m, 5H), 1.60-1.52 (m, 2H) 1569

MS (ESI) m/z 618.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 614.24 (bs, 1H),13.11 (bs, 1H), 9.17 (s, 1H), 8.79 (d, J = 4.80 Hz, 1H), 8.67 (s, 1H),8.52 (d, J = 7.20 Hz, 2H), 7.76 (d, J = 8.00 Hz, 1H), 7.71-7.68 (m, 2H),7.53 (d, J = 4.80 Hz, 1H), 7.38 (d, J = 7.20 Hz, 2H), 4.89 (s, 2H), 3.69(s, 3H), 2.23 (s, 3H) 1571

MS (ESI) m/z 665.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H),8.82 (d, J = 4.4 Hz, 1H), 8.35 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz,1H), 7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.36 (d, J =8.8 Hz, 1H), 6.55 (t, J = 53.2 Hz, 1H), 4.40 (d, J = 4.4 Hz, 2H), 4.26(s, 2H), 3.87 (bs, 1H), 3.47-3.24 (m, 4H), 2.00- 1.89 (m, 4H),1.78 (s,3H), 1.74-1.67 (m, 2H) 1568

MS (ESI) m/z 636.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.18 (bs,1H), 8.84 (s, 1H), 8.75 (d, J = 4.8 Hz,1H), 8.65 (s, 1H), 7.75 (d, J =8.4 Hz, 1H), 7.70-7.65 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H),4.38 (m, 2H), 3.79 (m, 2H,), 3.49 (m, 4H), 3.03 (m, 1H), 2.14 (s, 3H),0.93 (m, 4H) 1573

MS (ESI) m/z 685.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 7.77-7.75 (m, 1H), 7.70-7.68 (m,2H), 7.55 (d, J = 4.4 Hz, 1H), 6.60 (bs, 1H), 6.41 (s, 1H), 4.86 (s,2H), 3.99- 3.58 (m, 2H), 3.03-2.76 (m, 4H), 2.54 (s, 3H), 2.29-2.14 (m,5H), 1.77-1.75 (m, 1H) 1574

MS (ESI) m/z 659.38 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H),8.77 (d, J = 4.8 Hz, 1H), 8.60 (s, 1H), 7.76 (d, J = 18.4 Hz, 1H), 7.70(d, J = 2.0 Hz, 1H), 7.55 (d, J = 4.8 Hz, 2H), 6.55 (t, J = 54.4 Hz,1H), 4.87 (s, 2H), 3.60- 2.87 (m, 7H), 2.17 (s, 3H), 2.04-1.73 (m, 4H)1572

MS (ESI) m/z 709.45 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H),8.77 (d, J = 4.8 Hz, 1H), 8.63 (s, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.70(dd, J = 6.4 Hz, 2.0 Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.89 (s, 2H),3.78-3.56 (m, 3H), II s ' 3.28-3.19 (m, 2H), 3.00-2.79 (m, 2H), 2.08 (s,3H), 1.98-1.85 (m, 4H) 1576

MS (ESI) m/z 714.55 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H),7.68-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.81-3.38 (m,5H), 3.08 (s, 3H), 2.82-2.70 (m, 2H), 2.43-2.33 (m, 2H), 2.06 (s,3H),1.68-1.53 (m, 7H) 1577

MS (ESI) m/z 714.49 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H),7.68-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.81-3.38 (m,5H), 3.08 (s, 3H), 2.82-2.70 (m, 2H), 2.43-2.33 (m, 2H), 2.06 (s, 3H),1.68-1.53 (m, 7H) 1575

MS (ESI) m/z 728.08 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H),8.76 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H),7.68-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.81-3.38 (m,5H), 3.08 (s, 3H), 2.82-2.70 (m, 2H), 2.43-2.33 (m, 2H), 2.06 (s, 3H),1.68-1.53 (m, 7H) 1579

MS (ESI) m/z 760.64 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.17 (s, 1H), 8.66 (s, 1H), 7.76-7.74 (m, 1H), 7.70-7.68(m, 2H), 7.56 (d, J = 4.8 Hz, 1H), 6.43-4.15 (m, 1H), 4.81 (s, 2H), 4.30(bs, 1H), 3.54 (bs, 4H), 3.08 (s, 3H), 2.05 (bs, 7H), 1.83- 1.67 (m,6H), 1.17 (bs, 3H) 1581

MS (ESI) m/z 702.52 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74-8.70 (m,2H), 8.37 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.67-7.64 (m, 2H), 7.44 (d,J = 4.4 Hz, 1H), 6.16 (t, J = 55.6 Hz, 1H), 4.89-4.84 (m, 3H), 3.081(bs, 4H), 2.80-2.72 (m, 2H), 2.33 (bs, 3H), 2.07-1.98 (m, 4H), 1.90 (bs,3H), 1.75-1.71 (m, 1H), 1.41 (t, J = 7.2 Hz, 1H) 1578

MS (ESI) m/z 771.57 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H),8.82 (d, J = 4.4 Hz, 2H), 8.78 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.72-7.67 (m, 2H), 7.63 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.77-4.75 (m,4H), 4.44-4.35 (m, 2H), 3.76-3.59 (m, 3H), 3.54 (s, 3H), 3.28- 3.19 (m,1H), 3.02 (bs, 2H), 2.15 (s, 4H), 1.99 (s, 3H), 1.15 (t, J = 6.8 Hz, 3H)1583

MS (ESI) m/z 744.52 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.70 (s, 1H), 8.66 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H),7.69-7.68 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.26-4.23 (m,1H), 3.12-3.09 (m, 4H), 2.93 (bs, 3H), 2.57-2.52 (m, 2H), 2.06 (s, 3H),1.89 (bs, 4H), 1.75-1.72 (m, 7H), 1.22 (bs, 2H) 1584

MS (ESI) m/z 724.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.01 (bs, 1H),8.76-8.74 (m, 2H), 8.64 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.70-7.67 (m,2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.74-7.56 (m, 3H),3.52-3.49 (m, 2H), 3.32-3.26 (m, 4H), 3.11 (s, 3H), 2.26-2.21 (m, 2H),2.10 (s, 3H), 2.03-1.91 (m, 8H) 1582

MS (ESI) m/z 778.66 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.73 (s, 1H), 8.65 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H),7.70-7.67 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.58 (bs,2H), 4.24 (bs, 2H), 3.11 (s, 3H), 2.94-2.67 (m, 6H), 2.32-2.08 (m, 9H)1586

MS (ESI) m/z 748.52 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.72 (s, 1H), 8.70 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H),7.70-7.62 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H), 4.48-4.30 (m,1H), 3.40-2.85 (m, 9H), 2.20-1.75 (m, 7H), 1.20 (s, 6H) 1587

MS (ESI) m/z 746.54 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.13 (bs,1H), 8.75 (d, J = 4.8 Hz, 1H), 8.70 (s, 1H), 8.65 (s, 1H), 7.75 (d, J =9.2 Hz, 1H), 7.68-7.67 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H),4.26 (bs, 1H), 3.09 (s, 3H), 3.04 (d, J = 10.8 Hz, 2H), 2.70-2.50(merged, 2H), 2.10-2.00 (m, 5H), 1.88-1.81 (m, 4H), 0.97 (s, 2H), 0.74(s, 2H) 1585

MS (ESI) m/z 722.42 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 7.76-7.74 (m, 1H), 7.69-7.68(m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.29-4.27 (m, 1H), 3.44(bs, 2H), 3.17-3.09 (m, 5H), 2.66 (bs, 2H), 2.05 (s, 3H), 1.94 (d, J =10.4 Hz, 2H),1.80 (d, J = 10.8 Hz, 2H) 1589

MS (ESI) m/z 791.49 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H),9.72 (bs, 1H), 8.81-8.78 (m, 3H), 7.77 (d, J = 8.4 Hz, 1H), 7.72-7.67(m, 2H), 7.62 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.59 (bs, 1H),3.82-3.45 (m, 6H), 3.30-2.95 (m, 9H), 2.20-2.14 (m, 4H), 1.99 (s, 3H)1590

MS (ESI) m/z 807.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H),8.80 (d, J = 5.2 Hz 1H), 8.78 (s, 1H), 8.75 (s, 1H), 7.77 (d, J = 8.4Hz, 1H), 7.70 (dd, J = 10.4 Hz, 2 Hz, 2H), 7.62 (d, J = 4.8 Hz, 1H),6.45 (t, J = 54.8 Hz, 1H), 4.82 (s, 2H), 4.50 (d, J = 6.8 Hz, 2H), 4.45(d, J = 6.8 Hz, 2H), 4.34-4.29 (m, 1H), 3.55 (s, 3H), 3.11 (s, 3H), 2.91(d, J = 10.8 Hz, 2H), 2.60-2.53 (m, 2H),1.96-1.85 (m, 7H) 1588

MS (ESI) m/z 760.61 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (bs,1H), 9.09 (bs, 1H), 8.80-8.70 (m, 2H), 8.65 (s, 1H), 7.75 (d, J = 8.40Hz, 1H), 7.71-7.63 (m, 2H), 7.54 (d, J = 4.00 Hz, 1H), 4.82 (s, 2H),4.56 (bs, 1H), 3.70- 3.50 (m, 4H), 3.20-3.20 (merged, 2H), 3.11 (s, 3H),2.41-2.20 (m, 6H), 2.18-1.94 (m, 7H) 1592

MS (ESI) m/z 714.10 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.09 (bs,1H), 8.75-8.74 (m, 2H), 8.64 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.69-7.67 (m, 2H), 7.53 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 4.39 (bs,2H), 4.01 (bs, 1H), 3.66 (bs, 1H), 3.20-2.95 (m, 5H), 2.72-2.66 (m, 2H),2.08 (bs, 5H), 1.90-1.60 (m, 4H) 1593

MS (ESI) m/z 851.58 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.03 (bs,1H), 8.87 (d, J = 4.80 Hz, 1H), 8.84 (s, 1H), 8.73 (s, 1H), 7.77 (d, J =9.20 Hz, 1H), 7.71-7.69 (m, 2H), 7.65 (d, J = 4.80 Hz, 1H), 5.06 (q, J =9.60 Hz, 2H), 4.82 (s, 2H), 4.32-4.29 (m, 1H), 3.33 (bs, 2H), 3.09 (bs,5H), 2.58 (bs, 2H), 1.96 (bs, 2H), 1.92 (s, 3H), 1.80 (d, J = 11.2 Hz,2H) 1591

MS (ESI) m/z 857.53 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =5.2 Hz, 1H), 8.81 (s, 1H), 8.75 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H),7.71-7.69 (m, 2H), 7.64 (d, J = 4.8 Hz, 1H), 6.73-6.58 (m, 1H),6.15-5.87 (m, 1H), 4.82 (s, 2H), 4.59-4.55 (m, 2H), 4.52-4.47 (m, 4H),4.35-4.22 (m, 4H), 3.16-3.04 (m, 3H), 2.86 (m, 1H), 1.92 (s, 3H), 1.76(d, J = 11.2 Hz, 2H), 1.56-1.48 (m, 2H) 1595

MS (ESI) m/z 847.0 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.06 (bs, 1H),8.85 (d, J = 4.8 Hz, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 7.78 (d, J = 8.80Hz, 1H), 7.71 (bs, 2H), 7.65 (d, J = 4.80 Hz, 1H), 5.04 (q, J = 9.60 Hz,2H), 4.83 (s, 2H), 4.59 (bs, 1H), 3.77 (bs, 4H), 3.37 (bs, 2H), 3.11 (s,3H), 2.26 (bs, 2H), 2.02 (bs, 2H), 1.95 (s, 3H), 1.76 (t, J = 17.6 Hz,3H) 1596

MS (ESI) m/z 701.0 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6 with D2O) 6 8.68(s, 1H), 8.67 (s, 1H), 8.39 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.65-7.63(m, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 4.8 Hz, 1H), 4.73 (s2H), 4.55-4.49 (m, 1H), 3.80-3.72 (m, 2H), 3.62-3.57 (m, 2H), 3.28 (t, J= 11.6 Hz, 2H), 3.09 (s, 1H), 2.53 (bs, 1H), 2.32-2.20 (m, 2H), 2.06(bs, 6H), 1.74 (t, J = 19.6 Hz, 3H) 1594

MS (ESI) m/z 705.48 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H),8.67 (s, 1H), 8.45 (s, 1H), 7.72 (d, J = 8.00 Hz, 1H), 7.65 (d, J = 8.40Hz, 1H), 7.61 (bs, 1H), 7.44 (d, J = 2.40 Hz, 1H), 4.76 (s, 2H), 4.32(t, J = 12.00 Hz, 1H), 3.49 (d, J = 8.80 Hz, 2H), 3.18 (d, J = 10.80 Hz,2H), 3.07 (s, 3H), 2.73 (t, J = 11.2 Hz, 2H), 2.02 (s, 3H), 1.96 (d, J =13.2 Hz, 2H), 1.85 (d, J = 10.8 Hz, 2H) 1598

MS (ESI) m/z 758.69 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.94 (bs, 1H),8.77 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H),7.69-7.67 (m, 2H), 7.55 (d, J = 4.4 Hz, 1H), 6.43 (bs, 1H), 4.82 (s,2H), 4.53 (bs, 1H), 3.79 (bs, 4H), 3.39-3.35 (m, 2H), 3.11 (s, 3H), 2.41(bs, 2H), 2.32-2.26 (m, 2H), 2.09 (s, 7H), 1.86-1.82 (m, 1H), 1.65-1.60(m, 1H) 1599

MS (ESI) m/z 638.41 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79-8.74 (m,2H), 8.65 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.55 (d,J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.54-4.53 (m, 1H), 3.58-3.55 (m, 2H),3.20 (bs, 2H), 3.01 (s, 3H), 2.83-2.82 (m, 3H), 2.10 (bs, 7H) 1597

MS (ESI) m/z 833.52 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.08 (bs,1H), 8.86-8.84 (m, 2H), 7.79-7.769 (m, 1H), 7.71 (t, J = 2.0 Hz, 2H),7.66 (d, J = 5.2 Hz, 1H), 6.51 (bs, 1H), 5.08-5.01 (m, 2H), 4.83 (s,2H), 4.52 (bs, 1H), 3.94 (bs, 2H), 3.41 (bs, 4H), 3.21 (s, 3H), 2.15(bs, 2H), 2.07 (s, 5H) 1601

MS (ESI) m/z 805.69 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 12.47 (bs,1H), 8.81 (d, J = 4.8 Hz, 1H), 8.78 (bs, 2H), 7.79 (d, J = 11.6 Hz, 1H),7.70 (bs, 1H), 7.68 (bs, 1H), 7.63 (d, J = 4.80 Hz, 1H), 4.82 (s, 2H),4.20 (bs, 1H), 3.65 (g, J = 6.80 Hz, 2H), 3.54 (s, 3H), 2.93-2.90 (m,2H), 2.69-2.66 (m, 4H), 2.42-2.32 (m, 3H), 1.94 (s, 3H), 1.92-1.89 (m,4H) 1.11 (t, J = 6.8 Hz, 3H) 1602

MS (ESI) m/z 773.67 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H),9.72 (bs, 1H), 8.81-8.78 (m, 3H), 7.77 (d, J = 8.36 Hz, 1H), 7.72-7.67(m, 2H), 7.62 (d, J = 4.80 Hz, 1H), 5.33-5.14 (dm, 1H), 4.83 (s, 2H),4.63-4.55 (m, 1H), 4.03-3.97 (m, 1H), 3.60-3.50 (merged, 3H), 3.11 (s,3H), 3.09-3.02 (m, 2H), 2.76-2.50 (m, 6H), 2.12-2.07 (m, 4H), 1.99 (s,3H) 1600

MS (ESI) m/z 678.56 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.12 (bs,1H), 8.83-8.73 (m, 3H), 8.66 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H),7.70-7.68 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.40 (bs,1H), 3.71-3.57 (m, 4H), 3.40-3.20 (merged, 2H), 2.85 (bs, 1H), 2.18-2.00 (m, 7H), 1.14 (t, J = 6.4 Hz, 3H), 0.98-0.79 (m, 4H) 1604

MS (ESI) m/z 793.67 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.73 (bs, 2H), 7.78 (d, J = 8.4 Hz, 1H),7.71-7.69 (m, 2H), 7.63 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.61 (bs,1H), 3.84 (bs, 1H), 3.69-3.65 (m, 2H), 3.11 (s, 3H), 2.02-1.91 (m, 6H),1.76 (bs, 4H), 1.38 (t, J = 14.4 Hz, 3H) 1605

MS (ESI) m/z 793.67 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.73 (bs, 2H), 7.78 (d, J = 8.4 Hz, 1H),7.71-7.69 (m, 2H), 7.63 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.61 (bs,1H), 3.84 (bs, 1H), 3.69-3.65 (m, 2H), 3.11 (s, 3H), 2.02-1.91 (m, 6H),1.76 (bs, 4H), 1.38 (t, J = 14.4 Hz, 3H) 1603

MS (ESI) m/z 833.74 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 9.86 (bs, 1H),8.80-8.78 (d, J = 8.80 Hz, 2H), 8.68 (s, 1H), 7.80-7.67 (m, 4H), 4.88(s, 2H), 4.54 (bs, 1H), 3.66-3.38 (m, 4H), 3.33-3.27 (m, 2H), 3.09 (s,3H), 2.40-2.25 (m, 2H), 2.12 (s, 3H), 2.10-1.99 (m, 2H), 1.76 (t, J =19.2 Hz, 3H) 1607

MS (ESI) m/z 829.71 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H),8.81 (d, J = 4.8 Hz, 1H), 8.78 (d, J = 3.0 Hz, 2H), 7.77 (d, J = 8.16Hz, 1H), 7.70-7.68 (m, 2H), 7.49 (d, J = 6.36 Hz, 1H), 6.56 (tt, J =4.16 Hz, J = 88.08 Hz, 1H), 4.82 (s, 2H), 4.22-4.16 (m, 1H), 3.65 (d, J= 6.88 Hz, 2H), 3.55 (s, 3H) 3.04-2.94 (m, 4H), 2.49-2.41 (m, 2H),1.99-1.89 (m, 5H), 1.78 (d, J = 10.68 Hz, 2H), 1.11 (t, J = 6.72 Hz, 3H)1608

MS (ESI) m/z 871.79 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H),8.83 (d, J = 4.8 Hz, 1H), 8.78 (s, 1H), 8.72 (s, 1H), 7.77 (d, J = 8.16Hz, 1H), 7.71-7.69 (m, 2H), 7.64 (d, J = 4.84 Hz, 1H), 6.58 (tt, J =52.56 Hz, 5.4 Hz, 1H), 5.25-5.20 (m, 1H), 4.98-4.92 (m, 4H), 4.82 (s,2H), 4.24 (bs, 1H), 3.95 (bs, 2H), 3.68-3.62 (m, 2H), 3.50-3.10 (m, 4H),2.01-1.97 (m, 2H), 1.90 (s, 3H), 1.86 (bs, 2H), 1.12 (t, J = 6.8 Hz, 3H)1606

MS (ESI) m/z 821.52 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H),8.80 (d, J = 4.84 Hz, 1H), 8.78 (d, J = 2.6 Hz, 2H), 7.77 (d, J = 8.31Hz, 1H), 7.71-7.67 (m, 2H), 7.62 (d, J = 4.80 Hz, 1H), 4.76 (s, 2H),4.60-4.57 (m, 1H), 3.85-3.58 (m, 4H), 3.49 (s, 3H), 3.32 (t, J = 12 Hz,2H), 3.10 (s, 3H), 2.32-2.02 (m, 4H), 1.98 (s, 3H), 1.80-1.70 (m, 3H)1610

MS (ESI) m/z 881.27 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H),8.81 (d, J = 4.84 Hz, 1H), 8.77 (s, 1H), 8.76 (s, 1H), 7.77 (d, J = 8.36Hz, 1H), 7.72-7.67 (m, 2H), 7.62 (d, J = 4.84 Hz, 1H), 5.20-5.16 (m,1H), 4.97- 4.89 (m, 4H), 4.82 (s, 2H), 4.75-4.70 (m, 1H), 4.61-4.57 (m,1H), 3.54-3.51 (m, 2H), 3.54-3.43 (m, 3H), 3.11 (s, 3H), 3.08-3.06 (m,2H), 2.87- 2.83 (m, 2H), 2.11-2.08 (m, 4H), 1.95 (s, 3H) 1611

MS (ESI) m/z 902.74 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H),8.89 (d, J = 4.80 Hz, 1H), 8.72 (d, J = 4.40 Hz, 1H), 8.64 (s, 1H), 8.61(s, 1H), 8.27-8.25 (m, 1H), 8.22-8.18 (m, 1H), 7.77-7.73 (m, 2H),7.71-7.69 (m, 2H), 7.65 (d, J = 4.80 Hz, 1H), 4.83 (s, 2H), 4.75- 4.70(m, 1H), 4.58 (bs, 1H), 3.67 (bs, 3H), 3.54 (d, J = 10.80 Hz, 2H),3.42-3.38 (m, 1H), 2.86- 2.84 (m, 2H), 2.85 (bs, 2H), 2.45-2.40 (m, 2H),2.08 (bs, 4H), 1.95 (s, 3H) 1609

MS (ESI) m/z 892.75 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H),8.91 (d, J = 4.4 Hz, 1H), 8.72 (d, J = 3.6 Hz, 1H), 8.65 (s, 1H), 8.60(s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.21 (t, J = 7.6 Hz, 1H), 7.77-7.75(m, 2H), 7.70-7.66 (m, 3H), 6.58 (t, J = 52.8 Hz, 1H), 4.82 (s, 2H),4.23 (bs, 1H), 3.62 (d, J = 7.2 Hz, 2H), 3.16- 3.12 (m, 4H), 2.53 (s,2H), 2.01 (bs, 2H), 1.90- 1.84 (m, 5H), 1.09 (t, J = 6.4 Hz, 3H) 1617

MS (ESI) m/z 730.46 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 with D2O) 6 8.67(bs, 2H), 7.95 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.28 (s,1H), 7.21 (bs, 2H), 6.28 (m, J = 53.6 Hz, 1H), 4.30 (bs, 2H), 4.21-4.00(m, 3H), 3.29-3.19 (m, 4H), 2.99 (s, 3H), 2.80 (bs, 2H), 2.03 (bs, 2H),1.86 (bs, 2H), 1.64 (s, 3H) 1618

MS (ESI) m/z 791.49 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H),9.72 (bs, 1H), 8.81-8.78 (m, 3H), 7.77 (d, J = 8.4 Hz, 1H), 7.72-7.67(m, 2H), 7.62 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 4.59 (bs, 1H),3.82-3.45 (m, 6H), 3.30-2.95 (m, 9H), 2.20-2.14 (m, 4H), 1.99 (s, 3H)1616

MS (ESI) m/z 786.58 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 with D2O) 6 8.77(d, J = 4.40 Hz, 1H), 8.68 (s, 1H), 8.19 (d, J = 9.60 Hz, 1H), 7.52 (dd,J = 2.2, 8.8 Hz, 1H), 7.35-7.26 (m, 3H), 6.24 (t, J = 54.4 Hz, 1H),4.33-4.17 (m, 10H), 3.21 (bs, 3H), 3.03 (s, 3H), 2.70 (bs, 1H), 2.58(bs, 1H), 1.97 (bs, 2H), 1.82 (bs, 2H), 1.55 (s, 3H), 1.28 (t, J = 6.8Hz, 6H) 1621

LCMS: 603.6 [M + H]+; 1H NMR (400 MHz, Methanol-d4) 6 8.31 (s, 1H), 7.54(dd, J = 8.9, 2.6 Hz, 1H), 7.41 (s, 1H), 7.36-7.25 (m, 2H), 4.46 (t, J =5.1 Hz, 2H), 4.34 (t, J = 5.1 Hz, 2H), 3.13 (s, 6H), 2.89 (s, 3H), 2.83(s, 3H), 2.24 (s, 3H) 1622

LCMS (ESI) m/z 658.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H),7.69 (tt, J = 8.5, 6.6 Hz, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.48-7.43 (m, 2H), 7.40-7.32 (m, 3H), 4.43 (t, J = 5.0 Hz, 2H), 4.27 (t,J = 4.9 Hz, 2H), 2.81 (s, 3H), 2.69 (s, 3H), 1.88 (s, 3H) 1620

MS (ESI) m/z 726.41 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.0 Hz, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 7.58 (d, J = 7.2, 1H),7.39-7.33 (m, 3H), 4.37 (bs, 2H), 4.25 (bs, 3H), 3.91 (s, 3H), 3.3;2-3.30 (m, 2H), 3.07-2.72 (m, 5H), 2.44-2.32 (m, 2H), 1.93-1.74 (bs,4H), 1.69 (s, 3H) 1624

LCMS (ESI) m/z 662.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =4.8 Hz, 1H), 8.46 (s, 1H), 7.57 (dd, J = 9.0, 2.6 Hz, 1H), 7.44 (d, J =4.8 Hz, 1H), 7.39-7.32 (m, 2H), 4.98-4.74 (m, 2H), 4.40 (t, J = 5.1 Hz,2H), 4.29 (s, 1H), 4.21 (t, J = 5.1 Hz, 2H), 3.64 (s, 3H), 3.56 (s, 1H),3.47 (s, 1H), 3.31 (s, 2H), 2.63 (s, 3H), 1.86 (s, 3H) 1625

MS (ESI) m/z 805.29 [M + 1]+ 1623

LCMS (ESI) m/z 644.1 [M + 1]+; 1H NMR (400 MHz, Chloroform-d) δ 8.48 (s,1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.42-7.37 (m, 2H),4.42 (d, J = 5.3 Hz, 2H), 4.33 (s, 1H), 4.30 (s, 1H), 4.25 (d, J = 5.0Hz, 2H), 3.61 (d, J = 12.2 Hz, 2H), 3.44 (d, J = 13.6 Hz, 4H), 3.24 (d,J = 11.0 Hz, 1H), 2.92 (d, J = 4.4 Hz, 3H), 2.73 (s, 3H), 2.66 (s, 4H),1.98 (s, 3H) 1627

MS (ESI) m/z 602.29 [M + 1]+ 1628

MS (ESI) m/z 608.3 [M + 1]+ 1626

LCMS (ESI) m/z 599.2 [M + 1]+ 1630

MS (ESI) m/z 618.09 [M + 1]+ 1631

1629

1633

LCMS (ESI) m/z 608.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J =4.7 Hz, 2H), 8.63 (s, 1H), 8.47 (s, 2H), 7.72 (dd, J = 8.1, 0.8 Hz, 1H),7.68-7.61 (m, 2H), 7.50 (d, J = 4.8 Hz, 1H), 4.77 (s, 2H), 4.54 (s, 4H),4.20 (t, J = 6.2 Hz, 4H), 2.06 (s, 3H), 1.20 (s, 1H) 1634

MS (ESI) m/z 678.5 [M + 1]+ 1632

LCMS (ESI) m/z 469.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77-8.71 (m,2H), 8.66 (s, 1H), 7.75 (dd, J = 8.1, 0.8 Hz, 1H), 7.72-7.64 (m, 2H),7.54 (d, J = 4.9 Hz, 1H), 4.81 (s, 2H), 4.63 (s, 2H), 4.53 (s, 2H), 4.44(s, 2H), 4.39 (s, 2H), 3.36 (s, 4H), 2.73-2.62 (m, 1H), 2.10 (s, 3H)1636

MS (ESI) m/z 619.45 [M + 1]+ 1637

MS (ESI) m/z 638.39 [M + 1]+ 1635

MS (ESI) m/z 688.48 [M + 1]+ 1639

MS (ESI) m/z 706.46 [M + 1]+ 1640

1638

MS (ESI) m/z 670.50 [M + 1]+ 1642

MS (ESI) m/z 710.46 [M + 1]+ 1643

MS (ESI) m/z 706.47 [M + 1]+ 1641

MS (ESI) m/z 706.55 [M + 1] 1645

MS (ESI) m/z 628.46 [M + 1]+ 1646

MS (ESI) m/z 668.45 [M + 1]+ 1644

MS (ESI) m/z 690.47 [M + 1]+ 1648

LCMS: 2.01 Min, 777.3 [M + H]+ 1649

MS (ESI) m/z = 706.48 [M + 1]+ 1647

MS (ESI) m/z 706.46 [M + 1]+ 1651

1652

1650

MS (ESI) m/z 720.47 [M + 1]+ 1654

MS (ESI) m/z, 690.46 [M + 1]+ 1655

MS (ESI) m/z 704.57 [M + 1]+ 1653

MS (ESI) m/z 670.43 [M + 1]+ 1657

1658

1656

1660

1661

1659

1663

MS (ESI) m/z 688.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J =4.8 Hz, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 7.74-7.71 (m, 1H), 7.67-7.63(m, 2H), 7.52 (d, J = 4.8 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.80 (tt, J= 52.4, 3.5 Hz, 1H), 4.78 (s, 2H), 4.55-4.40 (m, 1H), 4.02 (td, J =14.3, 3.9 Hz, 2H), 3.69-3.60 (m, 4H), 3.25(s, 3H), 2.32-2.18 (m, 2H),2.10-2.01 (m, 2H), 2.00 (s, 3H).   1664

1662

MS (ESI) m/z 708.54 [M + 1]+ 1666

1672

1676

1665

MS (ESI) m/z = 714.5 [M + 1]+ 1669

1670

1667

1668

1673

1671

1675

1677

1674

1678

1679

1680

1681

1683

1687

1684

1686

1690

MS (ESI) m/z 728.47 [M + 1]+ 1682

1685

1688

MS (ESI) m/z 720.47 [M + 1]+ 1689

MS (ESI) m/z 714.45 [M + 1]+ 1691

MS (ESI) m/z 714.55 [M + 1]+ 1697

1700

1693

1694

1702

1692

1696

1695

1699

1701

1698

1706

MS (ESI) m/z 878.31 [M + 1]+ 1703

MS (ESI) m/z 815.32 [M + 1]+ 1704

MS (ESI) m/z 857.25 [M + 1]+ 1705

MS (ESI) m/z 878.28 [M + 1]+ 1707

1711

1708

1709

1710

1714

1712

1713

1715

1716

1717

MS (ESI) m/z 762.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.75 (s, 1H), 8.65 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H),7.71-7.66 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 7.26 (s, 1H), 4.83 (s, 2H),4.68-4.55 (m, 1H), 4.22 (d, J = 13.7 Hz, 1H), 3.99-3.71 (m, 7H), 3.20(s, 3H), 2.70-2.61 (m, 2H), 2.42- 2.30 (m, 2H), 2.18-2.00 (m, 5H) 1721

1719

1723

MS (ESI) m/z 726.28 [M + 1]+ 1718

1720

1725

MS (ESI) m/z 732.19 [M + 1]+ 1722

MS (ESI) m/z 817.25 [M + 1]+ 1724

MS (ESI) m/z 732.18 [M + 1]+ 1728

MS (ESI) m/z 809.32 [M + 1]+ 1726

MS (ESI) m/z 823.30 [M + 1]+ 1727

MS (ESI) m/z 732.19 [M + 1]+ 1729

MS (ESI) m/z 823.3 [M + 1]+ 1732

MS (ESI) m/z 837.31 [M + 1]+ 1730

MS (ESI) m/z 746.28 [M + 1]+ 1731

MS (ESI) m/z 823.27 [M + 1]+ 1735

MS (ESI) m/z 796.33 [M + 1]+ 1733

MS (ESI) m/z 785.26 [M + 1]+ 1734

MS (ESI) m/z 839.26 [M + 1]+ 1738

MS (ESI) m/z 848.33 [M + 1]+ 1736

MS (ESI) m/z 810.23 [M + 1]+ 1737

MS (ESI) m/z 838.32 [M + 1]+ 1741

MS (ESI) m/z 834.32 [M + 1]+ 1739

MS (ESI) m/z 847.32 [M + 1]+ 1740

MS (ESI) m/z 834.36 [M + 1]+ 1744

MS (ESI) m/z 825.21 [M + 1]+ 1742

MS (ESI) m/z 834.31 [M + 1]+ 1743

MS (ESI) m/z 788.18 [M + 1]+ 1747

MS (ESI) m/z 813.29 [M + 1]+ 1745

MS (ESI) m/z 821.25 [M + 1]+ 1746

MS (ESI) m/z 799.24 [M + 1]+ 1750

MS (ESI) m/z 813.22 [M + 1]+ 1748

MS (ESI) m/z 811.27 [M + 1]+ 1749

MS (ESI) m/z 797.29 [M + 1]+ 1753

MS (ESI) m/z 785.32 [M + 1]+ 1751

MS (ESI) m/z 771.31 [M + 1]+ 1752

MS (ESI) m/z 708.23 [M + 1]+ 1756

MS (ESI) m/z 821.28 [M + 1]+ 1754

MS (ESI) m/z 799.34 [M + 1]+ 1755

MS (ESI) m/z 821.31 [M + 1]+ 1757

MS (ESI) m/z 835.45 [M + 1]+ 1758

MS (ESI) m/z 758.28 [M + 1]+ 1759

MS (ESI) m/z 835.26 [M + 1]+ 1760

MS (ESI) m/z 849.43 [M + 1]+ 1761

LCMS (ESI) m/z 821.4 [M + 1]+ 1762

LCMS (ESI) m/z 863.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.72 (s,1H), 9.53 (d, J = 9.3 Hz, 1H), 8.83 (d, J = 4.9 Hz, 1H), 8.78 (d, J =6.8 Hz, 2H), 7.78 (dd, J = 8.3, 0.5 Hz, 1H), 7.77-7.66 (m, 2H), 7.64 (d,J = 4.9 Hz, 1H), 6.73 (t, J = 21 Hz, 1H), 5.21 (tt, J = 7.8, 6.2 Hz,1H), 5.00-4.89 (m, 4H), 4.84 (s, 2H), 4.82- 4.74 (m, 1H), 4.60 (p, J =8.0 Hz, 1H), 3.94 (q, J = 7.8 Hz, 1H), 3.58 (d, J = 11.8 Hz, 2H), 3.13(s, 3H), 3.05 (s, 2H), 2.78-2.68 (m, 1H), 2.72 (s, 1H), 2.17-2.06 (m,4H), 1.97 (s, 3H) 1763

LCMS (ESI) m/z 884.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s,1H), 8.90 (d, J = 4.9 Hz, 1H), 8.72 (ddd, J = 4.7, 1.7, 1.0 Hz, 1H),8.63 (d, J = 13.4 Hz, 2H), 8.27 (dt, J = 7.9, 1.1 Hz, 1H), 8.24-8.16 (m,1H), 7.80-7.67 (m, 4H), 7.66 (d, J = 4.8 Hz, 1H), 6.72 (t, J = 76 Hz,1H), 4.83 (s, 2H), 4.78 (dt, J = 7.3, 3.8 Hz, 1H), 4.58 (d, J = 5.8 Hz,1H), 3.93 (q, J = 7.6 Hz, 1H), 3.56 (d, J = 11.8 Hz, 2H), 3.04 (s, 1H),2.72 (dd, J = 14.6, 7.1 Hz, 2H), 2.09 (s, 3H), 1.97 (s, 3H) 1764

LCMS (ESI) m/z 884.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.95-8.89 (m,2H), 8.82 (d, J = 4.9 Hz, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 8.07 76 Hz,1H) 4.81-4.71 (m, 2H), 4.55 (p, J = 8.0 Hz, 1H), 3.93-3.85 (m, 1H), 3.53(d, J = 11.7 Hz, 2H), 3.01 (s, 1H), 2.77-2.63 (m, 2H), 2.07 (s, 3H),1.90 (s, 2H), 1.90 (d, J = 16.7 Hz, OH) 1765

LCMS (ESI) m/z 884.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.24 (dd, J =2.5, 0.8 Hz, 1H), 8.89 (dd, J = 4.8, 1.6 Hz, 1H), 8.81 (d, J = 4.9 Hz,1H), 8.63 (s, 1H), 8.50 (ddd, J = 8.2, 2.4, 1.6 Hz, 1H), 8.46 (s, 1H),7.76-7.64 (m, 3H), 7.64-7.57 (m, 2H), 6.69 (t, J = 76 Hz, 1H), 4.76 (d,J = 10.9 Hz, 3H), 4.55 (t, J = 8.0 Hz, 1H), 3.94-3.85 (m, 1H), 3.52 (s,1H), 3.08 (s, 3H), 3.02 (s, 1H), 2.74-2.64 (m, 2H), 2.08 (s, 4H), 1.88(s, 3H) 1766

MS (ESI) m/z 758.34 [M + 1]+ 1767

MS (ESI) m/z 835.33 [M + 1]+ 1768

MS (ESI) m/z 877.29 [M + 1]+ 1769

MS (ESI) m/z 898.4 [M + 1]+ 1770

MS (ESI) m/z 898.26 [M + 1]+ 1771

MS (ESI) m/z 898.29 [M + 1]+ 1772

MS (ESI) m/z 839.28 [M + 1]+ 1773

MS (ESI) m/z 902.19 [M + 1]+ 1774

MS (ESI) m/z 902.23 [M + 1]+ 1775

MS (ESI) m/z 776.35 [M + 1]+ 1776

MS (ESI) m/z 853.3 [M + 1]+ 1777

MS (ESI) m/z 819.33 [M + 1]+ 1778

MS (ESI) m/z 895.27 [M + 1]+ 1779

MS (ESI) m/z 916.3 [M + 1]+ 1780

MS (ESI) m/z 916.27 [M + 1]+ 1781

MS (ESI) m/z 916.27 [M + 1]+ 1782

MS (ESI) m/z 762.31 [M + 1]+ 1783

MS (ESI) m/z 839.26 [M + 1]+ 1784

MS (ESI) m/z 776.29 [M + 1]+ 1785

MS (ESI) m/z 853.37 [M + 1]+ 1786

MS (ESI) m/z 760.31 [M + 1]+ 1787

MS (ESI) m/z 837.35 [M + 1]+ 1788

MS (ESI) m/z 851.42 [M + 1]+ 1789

MS (ESI) m/z 851.41 [M + 1]+ 1790

MS (ESI) m/z 865.46 [M + 1]+ 1791

MS (ESI) m/z 815.24 [M + 1]+ 1792

MS (ESI) m/z 836.27 [M + 1]+ 1793

MS (ESI) m/z 836.3 [M + 1]+ 1794

MS (ESI) m/z 836.33 [M + 1]+ 1795

MS (ESI) m/z 710.25 [M + 1]+ 1796

MS (ESI) m/z 787.34 [M + 1]+ 1797

MS (ESI) m/z 829.34 [M + 1]+ 1798

MS (ESI) m/z 850.31 [M + 1]+ 1799

MS (ESI) m/z 850.34 [M + 1]+ 1800

MS (ESI) m/z 850.25 [M + 1]+ 1801

MS (ESI) m/z 710.28 [M + 1]+ 1802

MS (ESI) m/z 787.28 [M + 1]+ 1803

MS (ESI) m/z 801.44 [M + 1]+ 1804

MS (ESI) m/z 797.32 [M + 1]+ 1805

MS (ESI) m/z 811.3 [M + 1]+ 1806

MS (ESI) m/z 770.31 [M + 1]+ 1807

MS (ESI) m/z 805.28 [M + 1]+ 1808

MS (ESI) m/z 819.358 [M + 1]+ 1809

MS (ESI) m/z 817.27 [M + 1]+ 1810

MS (ESI) m/z 831.26 [M + 1]+ 1811

MS (ESI) m/z 833.22 [M + 1]+ 1812

MS (ESI) m/z 833.39 [M + 1]+ 1813

MS (ESI) m/z 624.2 [M + 1]+ 1814

MS (ESI) m/z 843.32 [M + 1]+ 1815

MS (ESI) m/z 787.34 [M + 1]+ 1816

MS (ESI) m/z 850.31 [M + 1]+ 1817

MS (ESI) m/z 809.22 [M + 1]+ 1818

MS (ESI) m/z 845.26 [M + 1]+ 1819

MS (ESI) m/z 841.17 [M + 1]+ 1820

MS (ESI) m/z 817.25 [M + 1]+ 1821

MS (ESI) m/z 863.33 [M + 1]+ 1822

MS (ESI) m/z 863.38 [M + 1]+ 1823

MS (ESI) m/z 861.36 [M + 1]+ 1824

MS (ESI) m/z 895.39 [M + 1]+ 1825

MS (ESI) m/z 816.24 [M + 1]+ 1826

MS (ESI) m/z 830.3 [M + 1]+ 1827

MS (ESI) m/z 858.28 [M + 1]+ 1828

MS (ESI) m/z 833.34 [M + 1]+ 1829

MS (ESI) m/z 854.26 [M + 1]+ 1830

MS (ESI) m/z 854.26 [M + 1]+ 1831

MS (ESI) m/z 854.22 [M + 1]+ 1832

MS (ESI) m/z 868.26 [M + 1]+ 1833

MS (ESI) m/z 867.24 [M + 1]+ 1834

MS (ESI) m/z 811.4 [M + 1]+ 1835

MS (ESI) m/z 825.41 [M + 1]+ 1836

MS (ESI) m/z 819.33 [M + 1]+ 1837

MS (ESI) m/z 847.35 [M + 1]+ 1838

MS (ESI) m/z 868.26 [M + 1]+ 1839

MS (ESI) m/z 868.26 [M + 1]+ 1840

MS (ESI) m/z 868.29 [M + 1]+ 1841

MS (ESI) m/z 700.33 [M + 1]+ 1842

MS (ESI) m/z 777.26 [M + 1]+ 1843

MS (ESI) m/z 794.33 [M + 1]+ 1844

MS (ESI) m/z 796.44 [M + 1]+ 1845

MS (ESI) m/z 841.34 [M + 1]+ 1846

MS (ESI) m/z 805.38 [M + 1]+ 1847

MS (ESI) m/z 819.34 [M + 1]+ 1848

MS (ESI) m/z 823.3 [M + 1]+ 1849

MS (ESI) m/z 835.36 [M + 1]+ 1850

MS (ESI) m/z 730.34 [M + 1]+ 1851

MS (ESI) m/z 807.33 [M + 1]+ 1852

MS (ESI) m/z 730.36 [M + 1]+ 1853

MS (ESI) m/z 807.18 [M + 1]+ 1854

MS (ESI) m/z 746.16 [M + 1]+ 1855

MS (ESI) m/z 823.36 [M + 1]+ 1856

MS (ESI) m/z 730.37 [M + 1]+ 1857

MS (ESI) m/z 807.4 [M + 1]+ 1858

MS (ESI) m/z 807.3 [M + 1]+ 1589

MS (ESI) m/z 728.3 [M + 1]+ 1860

MS (ESI) m/z 805.32 [M + 1]+ 1861

MS (ESI) m/z 746.31 [M + 1]+ 1862

MS (ESI) m/z 823.39 [M + 1]+ 1863

MS (ESI) m/z 704.27 [M + 1]+ 1864

MS (ESI) m/z 781.26 [M + 1]+ 1865

MS (ESI) m/z 795.37 [M + 1]+ 1866

MS (ESI) m/z 718.34 [M + 1]+ 1867

MS (ESI) m/z 795.35 [M + 1]+ 1868

MS (ESI) m/z 809.44 [M + 1]+ 1869

MS (ESI) m/z 720.3 [M + 1]+ 1870

MS (ESI) m/z 797.35 [M + 1]+ 1871

MS (ESI) m/z 811.4 [M + 1]+ 1872

MS (ESI) m/z 728.26 [M + 1]+ 1873

MS (ESI) m/z 805.26 [M + 1]+ 1874

MS (ESI) m/z 819.46 [M + 1]+ 1875

MS (ESI) m/z 819.33 [M + 1]+ 1876

MS (ESI) m/z 746.28 [M + 1]+ 1877

MS (ESI) m/z 823.3 [M + 1]+ 1878

MS (ESI) m/z 746.34 [M + 1]+ 1879

MS (ESI) m/z 823.33 [M + 1]+ 1880

MS (ESI) m/z 756.29 [M + 1]+ 1881

MS (ESI) m/z 833.32 [M + 1]+ 1882

MS (ESI) m/z 738.34 [M + 1]+ 1883

MS (ESI) m/z 815.4 [M + 1]+ 1884

MS (ESI) m/z 692.31 [M + 1]+ 1885

MS (ESI) m/z 772.35 [M + 1]+ 1886

MS (ESI) m/z 849.4 [M + 1]+ 1887

MS (ESI) m/z 758.28 [M + 1]+ 1888

MS (ESI) m/z 835.26 [M + 1]+ 1889

MS (ESI) m/z 754.34 [M + 1]+ 1890

MS (ESI) m/z 831.29 [M + 1]+ 1891

MS (ESI) m/z 740.33 [M + 1]+ 1892

MS (ESI) m/z 817.32 [M + 1]+ 1893

MS (ESI) m/z 722.34 [M + 1]+ 1894

MS (ESI) m/z 799.27 [M + 1]+ 1895

MS (ESI) m/z 716.5 [M + 1]+ 1896

MS (ESI) m/z 716.33 [M + 1]+ 1897

MS (ESI) m/z 702.46 [M + 1]+ 1898

LCMS 1.90 (ESI) m/z 669.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz,1H), 7.50- 7.41 (m, 2H), 7.36 (s, 1H), 7.23- 7.09 (m, 2H), 4.40 (t, J =5.0 Hz, 2H), 4.24 (t, J = 4.9 Hz, 2H), 3.55 (d, J = 4.8 Hz, 2H),3.38-3.24 (m, 3H), 2.71-2.62 (m, 2H), 2.46 (s, 3H), 2.33 (p, J = 1.9 Hz,1H), 1.75 (s, 3H) 1982

MS (ESI) m/z 461.0 [M + 1]+ 1983

MS (ESI) m/z 497.0 [M + 1]+ 1984

MS (ESI) m/z 655.19 [M + 1]+ 1985

MS (ESI) m/z 734.34 [M + 1]+ 2020

MS (ESI) m/z 627.43 [M + 1]+ 2021

MS (ESI) m/z 806.23 [M + 1]+ 2022

MS (ESI) m/z 731.29 [M + 1]+ 2029

MS (ESI) m/z 746.25 [M + 1]+ 2023

MS (ESI) m/z 790.3 [M + 1]+ 2024

MS (ESI) m/z 713.31 [M + 1]+ 2025

MS (ESI) m/z 789.36 [M + 1]+ 2032

2030

MS (ESI) m/z 837.28 [M + 1]+ 2031

MS (ESI) m/z 705.34 [M + 1]+ 2041

MS (ESI) m/z 807.38 [M + 1]+ 2038

MS (ESI) m/z 718.1 [M + 1]+ 2039

MS (ESI) m/z 734.37 [M + 1]+ 2042

MS (ESI) m/z 807.38 [M + 1]+

Example 2. General Methods for Synthesizing 7-CF₃-Thienylpyridine andDerivative Compounds

The 7-CF₃-thienylpyridine and derivative compounds in Table 2 can besynthesized using methods described in Example 2. Many of the reactionsdescribed in Example 1 were used to synthesize compounds in Table 2. Forsome compounds, some of the reactions described in Example 3, below, canbe used to prepare the compounds.

Example 2A. Methods of Synthesizing the Left-Hand Side Example 2A.1

To a solution of diisopropyl amine (17.8 mL, 0.123 mol) in drytetrahydrofuran (200 mL) is added n-butyllithium (1.6 M, 66.5 mL, 0.113mol) drop wise at −78° C. under argon atmosphere. The reaction mixtureis warmed to −10° C. and stirred for 30 min. A solution of1-bromo-3-fluoro-5-(trifluoromethyl)benzene (1, 25.0 g, 0.102 mol) indry tetrahydrofuran (50 mL) is added at −78° C. and mixture stirred for45 min at −78° C. To this reaction mixture carbon dioxide gas is purgedfor 15 min and the temperature is gradually increased to roomtemperature in 2 h. After completion, the reaction mixture is cooled to−78° C. and quenched with ice water. The mixture is basified with 1 Naqueous sodium hydroxide solution and washed with diethyl ether. Theaqueous layer is acidified with 2 N hydrochloric acid to pH˜1 andextracted with ethyl acetate. The organic layer is separated, dried overanhydrous sodium sulphate, filtered and concentrated to afford2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid (2).

Example 2A.2

To a solution 2-bromo-6-fluoro-4-(trifluoromethyl)benzamide (3, 4.5 g,crude, 15.7 mmol) in N,N-dimethylformamide (40 mL), potassium carbonate(6.5 g, 47.2 mmol) and (2,4-dimethoxyphenyl)methanamine (3.1 mL, 20.45mmol) are added at room temperature. The reaction mixture is heated to50° C. and stirred for 16 h. After completion of reaction, the reactionmixture is poured into ice water and extracted with ethyl acetate Theorganic layer is washed with brine solution, dried over anhydrous sodiumsulphate, filtered, concentrated under reduced pressure to get crude.The crude is purified by column chromatography using 5% methanol indichloromethane as eluent. The desired fractions are concentrated underreduced pressure to afford2-bromo-6-((2,4-dimethoxybenzyl)amino)-4-(trifluoromethyl)benzamide (4).

To a solution of2-bromo-6-((2,4-dimethoxybenzyl)amino)-4-(trifluoromethyl)benzamide (4,1.0 g, 2.30 mmol) in dichloromethane (10 mL) is added trifluoroaceticacid (1.8 mL, 23.0 mmol), and the mixture is stirred for 30 min. Aftercompletion of reaction, the reaction mixture is concentrated, and theresulting crude is diluted with dichloromethane and washed withsaturated sodium bicarbonate solution, brine solution, dried overanhydrous sodium sulphate and concentrated under reduced pressure to getcrude. The crude is purified by column chromatography using 5% methanolin dichloromethane as eluent. The desired fractions are concentratedunder reduced to afford 2-amino-6-bromo-4-(trifluoromethyl)benzamide(5).

To a solution of 2-amino-6-bromo-4-(trifluoromethyl)benzamide (5, 2.0 g,7.06 mmol) in dichloromethane (20 mL) are added triethylamine (2.93 mL,21 mmol) and 2-fluoroacetyl chloride (1.0 mL, 14.1 mmol) at 0° C., andthe reaction mixture is stirred for 30 min at same temperature. Aftercompletion of reaction, the reaction mixture is diluted with ice waterand extracted with dichloromethane. The organic layer is washed withsaturated brine solution, dried over anhydrous sodium sulphate andconcentrated under reduced pressure to afford2-bromo-6-(2-fluoroacetamido)-4-(trifluoromethyl)benzamide (6).

To a solution of2-bromo-6-(2-fluoroacetamido)-4-(trifluoromethyl)benzamide (6, 0.600 g,1.749 mmol) in ethanol (5 mL) is added 5% sodium hydroxide (4.0 mL). Themixture is heated to 110° C. and stirred for 30 min. After completion ofreaction, the reaction mixture is neutralized with 1 N hydrochloric acidand extracted with ethyl acetate. The organic layer is washed withsaturated brine solution, dried over anhydrous sodium sulphate andconcentrated under reduced pressure to get crude product. The crudeproduct is purified by column chromatography using silica gel (100-200mesh) and 0-5% methanol in dichloromethane as eluent. The desiredfractions are concentrated under reduced pressure to afford5-bromo-2-(fluoromethyl)-7-(trifluoromethyl)quinazolin-4(3H)-one (7).

Example 2A.3

To a solution of7-bromo-6-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-5-carbonitrile(5, 0.200 g, 0.7 mmol) in N,N-dimethylformamide (2 mL), copper(I) iodide(0.159 g, 0.84 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate(5a, 0.403 g, 2.1 mmol) are added and reaction mixture is heated at 100°C. for 16 h. After completion, reaction mixture is cooled; water isadded to reaction mixture and extracted with ethyl acetate. The organiclayer is dried over anhydrous sodium sulphate, filtered and concentratedto afford6-fluoro-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(6).

Example 2A.4

A suspension of copper(I) bromide (89.8 g, 620.1 mmol) and tert-butylnitrite (63.8 mL, 620.1 mmol) in acetonitrile (2500 mL) is heated at 65°C. for 15 min. A solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline(1, 100 g, 387.6 mmol) in acetonitrile is added and heated the reactionmixture at 65° C. for 1 h. After completion, the reaction mass isquenched with water and extracted with ethyl acetate. The organic layeris dried over anhydrous sodium sulphate, filtered and concentrated underreduced pressure to get the crude material. The crude compound ispurified by column chromatography using 0-5% ethyl acetate in hexanesover silica gel (100-200 mesh) to afford1,2-dibromo-5-fluoro-3-(trifluoromethyl)benzene (2).

Example 2A.5

To a stirred solution of 4-fluoro-1-methyl-2-(trifluoromethyl)benzene(1, 1.05 g, 5.89 mmol) in TFA (4 mL) is added sulfuric acid (1.25 mL)and then N-bromosuccinimide (1.05 g, 5.89 mmol). The resulting mixtureis capped, covered in aluminum foil to keep light out, and stirred atroom temperature overnight. The reaction mixture is poured intovigorously stirred ice water and then extracted with hexanes. Theorganics are washed with brine, then saturated aqueous sodiumbicarbonate. The organics are dried over magnesium sulfate, filtered,concentrated on a rotary evaporator, and purified via silica gelchromatography (100% hexanes) to afford1-bromo-5-fluoro-2-methyl-3-(trifluoromethyl)benzene (2).

Example 2A.6

To a solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (1, 100.0g, 389.2 mmol) in acetonitrile (2500 mL) is added p-toluenesulfonic acid(220.9 g, 1160.1 mmol) portion wise at −10° C. A solution of sodiumnitrite (51.68 g, 750 mmol) and potassium iodide (157.7 g, 949.2 mmol)in water (100 mL) is added at −10° C. and the mixture is stirred for 45min at −10° C. After completion, the reaction mixture is quenched withwater & extracted with ethyl acetate (5000 mL). The organic layer iswashed with aqueous saturated sodium thiosulphate (500 mL). Organiclayer is separated, dried over anhydrous sodium sulphate, filtered andconcentrated to afford1-bromo-5-fluoro-2-iodo-3-(trifluoromethyl)benzene (2).

To a solution of 1-bromo-5-fluoro-2-iodo-3-(trifluoromethyl) benzene (2,80.0 g, 217.3 mmol) in N,N-dimethylformamide (500 mL), copper(I) cyanide(19.4 g, 217.2 mmol) is added at room temperature. The reaction mixtureis stirred at 90° C. for 12 h. After completion, it is cooled to roomtemperature, poured into ice water and extracted with ethyl acetate (2.0L). The organic layer is washed with brine solution, dried overanhydrous sodium sulphate and concentrated under reduced pressure to getcrude. The crude compound is purified by flash column chromatographyusing 0-5% ethyl acetate in hexanes to afford2-bromo-4-fluoro-6-(trifluoromethyl)benzonitrile (3).

To a solution 2-bromo-4-fluoro-6-(trifluoromethyl)benzonitrile (3, 12.0g, 44.9 mmol) in tetrahydrofuran (200 mL), borane in tetrahydrofuran (1M, 67 mL, 67.1 mmol) is added drop wise at 0° C. The reaction mixture isallowed to stir at 90° C. for 12 h. After completion, the reactionmixture is poured into chilled methanol and concentrated under reducedpressure. The crude compound is purified by flash column chromatographyusing 0-15% ethyl acetate in hexanes to afford(2-bromo-4-fluoro-6-(trifluoromethyl) phenyl)methanamine (4).

To a solution of (2-bromo-4-fluoro-6-(trifluoromethyl)phenyl)methanamine (4, 6.0 g, 22.6 mmol) in methanol (100 mL),paraformaldehyde (6.0 g, 200.0 mmol) and solution of sodium acetate (5.4g, 66.0 mmol) in water (10 mL) are added and stirred at room temperaturefor 1 h. Sodium cyanoborohydride (4.03 g, 66.1 mmol) is added portionwise at 0° C. The reaction mixture is allowed to stir at roomtemperature for 12 h. After completion, the reaction mixture isconcentrated under reduced pressure. Crude residue is diluted with waterand extracted with diethyl ether (100 mL). The crude compound ispurified by flash column chromatography using 0-15% ethyl acetate inhexanes to afford1-(2-bromo-4-fluoro-6-(trifluoromethyl)phenyl)-N,N-dimethylmethanamine(5).

Example 2A.7

To a solution of5-bromo-6-(hydroxymethyl)-2-methyl-7-(trifluoromethyl)quinazolin-4(3H)-one(A, 0.32 g, 0.94 mmol) in dichlomethane (6 mL) at 0° C., triethyl amine(0.39 mL, 2.84 mmol) and methanesulfonyl chloride (0.11 mL, 1.42 mmol)are added and stirred at 0° C. for 1 h. After completion, the reactionmixture is diluted with water and extracted with dichloromethane. Theorganic layer is washed with water, saturated brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford5-bromo-6-(chloromethyl)-2-methyl-7-(trifluoromethyl)quinazolin-4(3H)-one(1)

To a solution of 4,4-difluoro piperidine (1a, 2.0 g, 12.7 mmol) inN,N-dimethylformamide (10.0 mL) is added potassium carbonate (1.06 g,7.62 mmol) at room temperature and the mixture is stirred for 20 min.Then5-bromo-6-(chloromethyl)-2-methyl-7-(trifluoromethyl)quinazolin-4(3H)-one(1, 0.9 g, 2.54 mmol) is added to the reaction mixture at roomtemperature and stirring is continued for 24 h. After completion, thereaction mixture is diluted with water and extracted with ethyl acetate.The organic layer is washed with water and saturated brine solution,dried over anhydrous sodium sulphate, filtered and concentrated. Thecrude product is purified by column chromatography using silica gel(100-200 mesh) and 50% ethyl acetate in hexane as eluent. The desiredfractions are concentrated under reduced pressure to afford5-bromo-6-((4,4-difluoropiperidin-1-yl)methyl)-2-methyl-7-(trifluoromethyl)quinazolin-4(3H)-one(2).

Example 2A.8

To a solution of6-bromo-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(1, 50 mg, 0.151 mmol) in tetrahydrofuran (3 mL) and water (0.75 mL) areadded 1-methyl-4-((trifluoro-λ⁴-boranyl)methyl)piperazine, potassiumsalt (1a, 497 mg, 2.25 mmol), cesium carbonate (196 mg, 0.602 mmol) andXPhosChloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(24 mg, 0.0301 mmol) and the mixture is sparged with argon for 5 min,then it is sealed and heated to 80° C. for 15 h. After completion, themixture is concentrated under reduced pressure to get crude product. Thecrude product obtained is purified by prep-HPLC to afford2-methyl-6-((4-methylpiperazin-1-yl)methyl)-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(2).

Example 2A.9

A solution of6-bromo-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(1, 1.00 g, 3.02 mmol), tert-butyl 4-methylenepiperidine-1-carboxylate(1a, 5.90 g, 30.1 mmol), triethylamine (1.20 mL, 9.03 mmol), and tri(o-tolyl)phosphine (0.366 g, 1.23 mmol) in acetonitrile (10.0 mL) isdegassed with argon for 10 min. Palladium (II) acetate (0.134 g, 0.60mmol) is then added to the reaction mixture and degassing is continuedfor 5 min. The reaction mixture is heated at 90° C. for 24 h. After thistime, the reaction mixture is cooled to room temperature, diluted withethyl acetate, and concentrated to dryness under reduced pressure. Thecrude product is purified by silica gel (100-200 mesh) columnchromatography using 30-50% ethyl acetate in hexanes as eluent. Thedesired fractions are concentrated under reduced pressure to affordtert-butyl4-((5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-6-yl)methylene)piperidine-1-carboxylate(2).

To a solution of tert-butyl4-((5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-6-yl)methylene)piperidine-1-carboxylate(2, 0.90 g, 2.0 mmol) in methanol (20 mL) is added 10% palladium oncarbon (1.35 g) at room temperature. The reaction mixture is stirred atroom temperature for 2 h under hydrogen atmosphere. Then, the reactionmixture is filtered with Celite. The filtrate is washed with ethylacetate and concentrated to dryness under reduced pressure to obtain acrude product. The crude product is purified by silica gel (100-200mesh) column chromatography using 3-5% methanol in dichloromethane aseluent. The desired fractions are concentrated under reduced pressure toafford tert-butyl4-((5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazolin-6-yl)methyl)piperidine-1-carboxylate(3).

Example 2A.10

To a solution of 4-fluoro-2-(trifluoromethyl)aniline (1, 100.0 g, 558.66mmol) in N,N-dimethylformamide (500 mL), N-chlorosuccinamide (78.7 g,558.66 mmol) is added at room temperature. This reaction mixture isstirred for 16 h. After this time, the mixture is diluted with water andextracted with ethyl acetate. The organic layer is washed with water andthen brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude product is purified by silica gel (100-200 mesh)column chromatography using hexanes as eluent. The desired fractions areconcentrated under reduced pressure to afford2-chloro-4-fluoro-6-(trifluoromethyl)aniline (2).

To a solution of 2-chloro-4-fluoro-6-(trifluoromethyl)aniline (2, 43.0g, 201.87 mmol) in acetonitrile (200 mL) at −10° C., p-toluenesulfonicacid monohydrate (115.0 g, 605.63 mmol) is added. This reaction mixtureis stirred for 15 min at the same temperature. A solution of sodiumnitrite (27.85 g, 403.74 mmol) and potassium iodide (83.77 g, 504.67mmol) in water (50 mL) is added dropwise to the reaction mixture as itis stirred at −10° C. for 30 min. Next, the reaction mixture is dilutedwith water and extracted with ethyl acetate. The organic layer is washedwith aqueous saturated sodium thiosulfate solution and then brine, driedover anhydrous sodium sulfate, filtered, and concentrated. The crudeproduct is purified by silica gel (100-200 mesh) column chromatographyusing hexanes as eluent. The desired fractions are concentrated underreduced pressure to afford1-chloro-5-fluoro-2-iodo-3-(trifluoromethyl)benzene (3).

To a solution of 1-chloro-5-fluoro-2-iodo-3-(trifluoromethyl)benzene (3,30 g, 92.6 mmol) in N,N-dimethylformamide (200 mL), copper(I) cyanide(12.36 g, 138.88 mmol) is added. This reaction mixture is heated at 100°C. for 16 h. After this time, the mixture is diluted with water andextracted with ethyl acetate. The organic layer is washed with water andbrine, dried over anhydrous sodium sulfate, filtered, and concentrated.The crude product is purified by silica gel (100-200 mesh) columnchromatography using 3% ethyl acetate in hexanes as eluent. The desiredfractions are concentrated under reduced pressure to afford2-chloro-4-fluoro-6-(trifluoromethyl)benzonitrile (4).

To a solution of 2-chloro-4-fluoro-6-(trifluoromethyl)benzonitrile (4,15.0 g, 67.26 mmol) in dry dichloromethane (150 mL) at −78° C.,diisobutylaluminiumhydride (1.0 M in toluene, 134.52 mL, 134.52 mmol) isadded dropwise. The mixture is stirred at same temperature for 30 min.Next, the reaction mixture is quenched with 1 N aqueous hydrochloricacid and extracted with dichloromethane. The organic layer is dried overanhydrous sodium sulfate, filtered, and concentrated to dryness underreduced pressure to afford2-chloro-4-fluoro-6-(trifluoromethyl)benzaldehyde (5).

To a solution of 2-chloro-4-fluoro-6-(trifluoromethyl)benzaldehyde (5,17.00 g, 75.22 mmol) in tetrahydrofuran (100 mL),2-methylpropane-2-sulfinamide (5a, 13.65 g, 112.83 mmol) and titaniumethoxide (34.30 mL, 150.44 mmol) are added dropwise at room temperature.This reaction mixture is stirred at the same temperature for 16 h. Afterthis time, the reaction mixture is quenched with aqueous ammoniumchloride solution, filtered with Celite, and washed with ethyl acetate.The filterate is concentrated and the crude residue is purified byCombi-flash (40 g, Redi-Sep column) using 20% ethyl acetate in hexanesas eluent. The desired fractions are concentrated under reduced pressureto afford(E)-N-(2-chloro-4-fluoro-6-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide(6).

Magnesium turnings (5.0 g) are added to dry tetrahydrofuran (50 mL)followed by iodine (0.002 g) and the mixture is heated to just aboveroom temperature. Then, 2-(2-bromoethyl)-1,3-dioxane (6a, 9.8 mL, 72.94mmol) is added and the mixture is heated till it became colorless. Then,this mixture is added dropwise to a solution of(E)-N-(2-chloro-4-fluoro-6-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide(6, 12.00 g, 36.47 mmol) in tetrahydrofuran (50 mL) at room temperature.The resulting mixture is stirred at room temperature for 1 h. Next, thereaction mixture is quenched with aqueous ammonium chloride solution andextracted with ethyl acetate. The organic layer dried over anhydroussodium sulfate and concentrated. The crude residue is purified byCombi-flash (40 g, Redi-Sep column) using 30% ethyl acetate in hexanesas eluent. The desired fractions are concentrated under reduced pressureto affordN-(1-(2-chloro-4-fluoro-6-(trifluoromethyl)phenyl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide(7).

A solution mixture ofN-(1-(2-chloro-4-fluoro-6-(trifluoromethyl)phenyl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide(7, 12.00 g, 26.96 mmol) in trifluroacetic acid in water (3:1, 180 mL)is stirred at room temperature for 16 h. After this time, the reactionmixture is quenched with aqueous sodium bicarbonate solution andextracted with ethyl acetate. The organic layer is dried over anhydroussodium sulfate, filtered, and concentrated. The solid residue isdissolved in methanol, after which sodium borohydrate (8.00 g, 269.66mmol) is added at 0° C. and the mixture is stirred at room temperaturefor 8 h. After this time, the reaction mixture is quenched with ice-coldwater and extracted with ethyl acetate. The organic layer is dried overanhydrous sodium sulfate, filtered, and concentrated to dryness underreduced pressure to afford2-(2-chloro-4-fluoro-6-(trifluoromethyl)phenyl)pyrrolidine (8).

Example 2A.11

To a solution of 2,3-difluoro-4-(trifluoromethyl)benzoic acid (1, 5 g,22.123 mmol) in N,N-dimethylformamide (50 mL), N-iodosuccinimide (7.43g, 33.185 mmol) is added and purged with argon for 20 min. Then,palladium acetate (1.48 g, 6.637 mmol) is added and reaction mixture isheated at 100° C. for 48 h. After completion, the reaction mixture iscooled, diluted with water and extracted with ethyl acetate. Thecombined organic layer is washed with cold water and brine solution,dried over anhydrous sodium sulphate, filtered and concentrated underreduced pressure to afford2,3-difluoro-6-iodo-4-(trifluoromethyl)benzoic acid (2).

Example 2B. Methods of Synthesizing the Right-Hand Side Example 2B.1

To a solution 2-bromo-4-chlorophenol (7, 50.0 g, 241.0 mmol) in aqueoussodium hydroxide (1 M) (1.0 L), tetra-n-butylammonium bromide (11.64 g,36.15 mmol) and potassium iodide (6.00 g, 36.15 mmol) are added.1,2-dibromoethane (8,165.6 g, 891.7 mmol) is added at 85° C. and stirredfor 16 h at the same temperature. After completion, the reaction mixtureis poured into water and extracted with ethyl acetate. Combined organiclayer are washed with water, brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure to get crude; the crude compoundis purified by flash column chromatography (using 0-5% ethyl acetate inhexanes) to afford 2-bromo-1-(2-bromoethoxy)-4-chlorobenzene (9).

Example 2B.2

A stirred solution of thieno[3,2-b]pyridin-7-ol (1, 2.0 g, 13.2 mmol) inphosphorous oxybromide (7.5 g, 26.4 mmol) and 1,2-dichloroethane isheated at 90° C. for 12 h. After completion of the reaction, the mixtureis cooled to room temperature and quenched with saturated aqueoussolution of sodium bicarbonate and extracted with ethyl acetate. Theorganic layer is washed with brine, dried over anhydrous sodiumsulphate, filtered and concentrated to afford7-bromothieno[3,2-b]pyridine (2).

To a stirred solution of 7-bromothieno[3,2-b]pyridine (2, 1.5 g, 7.04mmol) in dry tetrahydrofuran (20 mL), freshly prepared lithiumdiisopropylamide (2.0 M in hexane, 8.75 mL, 17.5 mmol) is added at −78°C. and the mixture is stirred at same temperature for 1 h.Hexachloroethane (2.0 mL, 8.44 mmol) is added drop wise and the reactionmixture is allowed to warm up to room temperature over 3 h. The reactionis quenched with aqueous ammonium chloride solution, diluted with waterand extracted with ethyl acetate. The organic layer is washed with waterand saturated brine solution, dried over anhydrous sodium sulphate,filtered and concentrated. The crude product is purified over a plug ofsilica gel eluting the compound with ethyl acetate in hexanes (0-10%).The desired fractions are concentrated under reduced pressure to afford7-bromo-2-chlorothieno[3,2-b]pyridine (3).

To a solution of 7-bromo-2-chlorothieno[3,2-b]pyridine (3, 0.5 g, 2.02mmol) in dry tetrahydrofuran (10 mL) and the mixture is cooled to −78°C. Lithium diisopropylamide (2 M, 1.5 mL, 3.03 mmol) is added drop wiseand the reaction mixture is stirred at −78° C. for 1 h. Carbon dioxidegas is purged through the reaction mass for 20 min at same temperatureand is stirred for 1 h at −78° C. The reaction mixture is slowly warmedto 0° C. and stirred for 30 min. After completion, reaction mixture isquenched with water and washed with ethyl acetate. Ethyl acetate layeris discarded and aqueous layer is acidified with aqueous solution ofcitric acid. It is then extracted with ethyl acetate. The organic layeris separated, dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to afford7-bromo-2-chlorothieno[3,2-b]pyridine-3-carboxylic acid (4).

Example 2B.3

To a stirred solution of 7-chlorothieno[3,2-b]pyridine (1, 1.5 g, 8.9mmol) in dry tetrahydrofuran (50 mL) is added drop wise lithiumdiisopropylamide (11.7 mL, 19.5 mmol) at −78° C. and the mixture isstirred at same temperature for 1 h. Iodine (2.25 g, 8.87 mmol dissolvedin tetrahydrofuran, 10 mL) is added drop wise and the reaction mixtureis allowed to warm up to room temperature over 4 h. It is quenched withaqueous solution of ammonium chloride and extracted with ethyl acetate.The organic layer is washed with water and saturated brine solution,dried over anhydrous sodium sulphate, filtered and concentrated todryness under reduced pressure. The crude product is purified byCombiflash (12 g, RediSep column) using 5-10% ethyl acetate in hexanesas eluent. The desired fractions are concentrated under reduced pressureto afford 7-chloro-2-iodothieno[3,2-b]pyridine (2).

To a solution of 7-chloro-2-iodothieno[3,2-b]pyridine (2, 1.0 g, 3.4mmol) in N,N-dimethylformamide (10 mL), N-bromo succinamide is added atroom temperature. The reaction mixture is heated and stirred at 70° C.for 12 h. After completion of the reaction, the mixture is diluted withwater and extracted with ethyl acetate. The organic layer is washed withwater and saturated brine solution, dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure. The crudeproduct is purified by Combiflash (12 g, RediSep column) using 5-10%ethyl acetate in hexanes as eluent. The desired fractions areconcentrated under reduced pressure to afford3-bromo-7-chloro-2-iodothieno[3,2-b]pyridine (3).

A suspension 3-bromo-7-chloro-2-iodothieno[3,2-b]pyridine (3, 1.0 g, 2.7mmol) and tributyl vinyl tin (1.01 mL, 3.21 mmol) in 1,4-dioxane (10 mL)is degassed using argon for 10 min.Tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.19 mmol) is added tothe reaction mixture at room temperature and the mixture is heated at100° C. for 1 h. After completion, the reaction mixture is cooled toroom temperature, diluted with water and extracted with ethyl acetate.The ethyl acetate layer is dried over sodium sulfate and concentrated todryness under reduced pressure. The crude product is purified over aplug of silica gel eluting the compound with ethyl acetate:hexanes(1-10%). The desired fractions are concentrated under reduced pressureto afford 3-bromo-7-chloro-2-vinylthieno[3,2-b]pyridine (4).

To a solution of 3-bromo-7-chloro-2-vinylthieno[3,2-b]pyridine (4, 0.6g, 2.19 mmol) in dry tetrahydrofuran (20 mL) is added drop wise n-Butyllithium (1.7 mL 1.3 M in hexanes, 2.19 mmol) at −78° C. and reactionmixture is stirred at the same temperature for 2 h. Carbon dioxide gasis purged through the reaction mixture at −78° C. for 30 min and thereaction mixture is stirred for 1 h at the same temperature. Thereaction mixture is slowly warmed to 0° C. and stirred for 30 min. Aftercompletion, reaction mixture is quenched with water and washed withethyl acetate. Ethyl acetate layer is discarded and aqueous layer isacidified with aqueous solution of citric acid and extracted with ethylacetate. The organic layer is separated, dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure to afford7-chloro-2-vinylthieno[3,2-b]pyridine-3-carboxylic acid (5).

Example 2B.4

Methyl 7-bromothieno[3,2-b]pyridine-3-carboxylate (1, 68.0 mg, 0.25mmol) and bis(trifluoromethylsulfinyloxy)zinc (1a, 139.8 mg, 0.50 mmol)are dissolved in dimethylsulfoxide (1.71 mL) in an oven-dried screwcapped vial equipped with a stir bar. The mixture is stirred vigorouslyat 0° C. while tert-butyl hydroperoxide (0.09 mL, 0.92 mmol) is addedslowly. After completion of addition the ice bath is removed and thereaction mixture is heated to 50° C. in a heating block for 2.5 h beforebeing cooled to room temperature. The reaction mixture is diluted withsaturated aqueous sodium bicarbonate and ethyl acetate. The layers areseparated and the aqueous phase extracted with ethyl acetate threetimes. The combined organic material is washed with brine and dried overmagnesium sulfate. The solids are filtered and solvent removed in vacuoto afford a crude residue that is purified via silica gel chromatography(5 to 40% ethyl acetate in hexanes), affording methyl7-bromo-2-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate (2).

Example 2B.5

A solution of tert-butyl 7-bromothieno[3,2-b]pyridine-3-carboxylate (1,150.0 mg, 0.480 mmol), (3-oxo-1λ{circumflex over( )}{3},2-benziodoxol-1-yl) acetate (417.5 mg, 0.950 mmol),2-(tert-butyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1a, 132.0 mg,0.720 mmol) and tris(2,2′-bipyridyl)dichloro-ruthenium(II)hexahydrate(35.7 mg, 0.048 mmol) in hexafluoroisopropanol (1.25 mL) is stirred atroom temperature and irradiated with a 60 watt household lamp positioned10 cm away from the vial for 24 h. After completion, reaction mixture isdiluted with dichloromethane and silica gel is added. The solvent isevaporated. The crude silica mixture is purified by flash chromatographyusing silica gel (100-200 mesh) using 0-10% methanol in dichloromethaneas eluent. The desired fractions are concentrated under reduced pressureto afford tert-butyl7-bromo-2-(tert-butyl)thieno[3,2-b]pyridine-3-carboxylate (2).

Example 2B.6

Methyl 7-chlorothieno[3,2-b]pyridine-3-carboxylate (1, 0.2 g, 0.88 mmol)is dissolved in dichloromethane (2.2 mL) in an oven-dried screw cappedvial equipped with a stir bar. The reaction mixture is stirred at roomtemperature while 3-chloroperbenzoic acid (0.24 g, 1.41 mmol) is addedin 4 portions over 2 min. After 24 h the reaction mixture is poured ontosilica gel and purification via silica gel chromatography (50-100% ethylacetate in hexanes, then 10% methanol in ethyl acetate) afforded7-chloro-3-(methoxycarbonyl)thieno[3,2-b]pyridine 4-oxide (2).

7-chloro-3-(methoxycarbonyl)thieno[3,2-b]pyridine 4-oxide (2, 0.12 g,0.47 mmol) is dissolved in dichloromethane (3.3 mL) in an oven-driedscrew capped vial equipped with a stir bar. The mixture is stirred atroom temperature while methanesulfonyl chloride (0.18 mL, 2.36 mmol)dropwise. After 3 h more methanesulfonyl chloride (0.18 mL, 2.36 mmol)is added dropwise. After 4.5 h the reaction mixture is warmed to 40° C.and stirred an additional 16 h before being cooled to room temperature.The reaction mixture is poured onto silica gel and purification viasilica gel chromatography (0-50% ethyl acetate in hexanes) affordedmethyl 5,7-dichlorothieno[3,2-b]pyridine-3-carboxylate (3).

Zinc chloride solution (0.5 M, 0.59 mL, 0.29 mmol) is dissolved intetrahydrofuran (1.0 mL) in an oven-dried screw capped vial equippedwith a stir bar. The reaction mixture is stirred at room temperaturewhile bromo(cyclopropyl)magnesium (0.59 mL, 0.29 mmol) solution is addedslowly. After 45 min a solution of methyl5,7-dichlorothieno[3,2-b]pyridine-3-carboxylate (3, 67.0 mg, 0.25 mmol)in tetrahydrofuran (1.5 mL) is added slowly. After 1 min Pd₂(dba)₃ (28.4mg, 0.03 mmol) and dppf (30.4 mg, 0.06 mmol) are added and the reactionmixture subsequently heated to 60° C. for 1 h. The reaction mixture iscooled to room temperature and poured onto saturated aqueous NH₄Cl. Theaq. phase is extracted with ethyl acetate three times. The combinedorganic material is washed with brine and dried over magnesium sulfate,filtered and solvent removed in vacuo to provide a brown oil.Purification via silica gel chromatography (8-29% ethyl acetate inhexanes) afforded methyl7-chloro-5-cyclopropylthieno[3,2-b]pyridine-3-carboxylate (4).

Example 2B.7

7-bromo-3-(methoxycarbonyl)thieno[3,2-b]pyridine 4-oxide (2, 148 mg,0.514 mmol) is dissolved in chloroform (10 mL) and POCl₃ (0.48 mL, 0.79g, 5.1 mmol) is added. The vial is sealed and the mixture is stirred at60° C. for 4 h, then over night at room temperature. Then the mixture isconcentrated, taken up in DCM, washed with NaHCO₃ (aq), dried (Na₂SO₄),filtered, and concentrated. The crude product (140 mg) is dissolved inTHF (9 mL) and sodium methanolate (25% in MeOH, 0.12 mL, 0.12 g, 0.52mmol) is added. The mixture is stirred at room temperature for 2.75 h,and another 0.13 mL NaOMe sln (25% in MeOH) are added. After 30 minanother 0.04 mL NaOMe sln (25% in MeOH) are added. After another 10 minanother 0.04 mL NaOMe sln (25% in MeOH) are added. Then the mixture isdiluted with DCM and washed with water. The organic phase is dried(Na₂SO₄), filtered, concentrated. Purification by column chromatographyyielded 23.9 mg of a 3:1 mixture of 3′ and 3.

Example 2B.8

To a solution of tert-butyl7-bromo-5-(bromomethyl)thieno[3,2-b]pyridine-3-carboxylate (2, 200.0 mg,0.491 mmol) in N,N-dimethylpyrrolidone (3 mL) is added tert-butylN-tert-butoxycarbonylcarbamate (160.1 mg, 0.736 mmol) and potassiumcarbonate (203.6 mg, 1.473 mmol) and the reaction mixture is stirred atroom temperature for 24 h. After completion, reaction mixture is dilutedwith dichloromethane and silica gel is added. The solvent is evaporated.The crude silica mixture is purified by Isco column chromatography using0-10% methanol in dichloromethane as eluent. The desired fractions areconcentrated under reduced pressure to afford tert-butyl5-[[bis(tert-butoxycarbonyl)amino]methyl]-7-bromo-thieno[3,2-b]pyridine-3-carboxylate(3).

Example 2B.9

A suspension of methyl7-bromo-5-methylthieno[3,2-b]pyridine-3-carboxylate (1, 3.50 g, 12.3mmol) in formalin (37-40%) 10 mL is irradiated in microwave at 120° C.for 1 h. After 1 h, the reaction mass is cooled and extracted with ethylacetate. The starting material is not consumed in 1 h, reaction isirradiated again after work-up 3 times under microwave. The reaction ismonitored by LCMS, still 50% starting material is remaining. Thereaction mass is cooled and extracted with ethyl acetate. The organiclayer is dried over anhydrous sodium sulfate and concentrated to drynessunder reduced pressure. The residue is purified by column chromatographyusing silica (100-200 mesh) and 0-40% ethyl acetate in hexane to affordmethyl 7-bromo-5-(2-hydroxyethyl)thieno[3,2-b]pyridine-3-carboxylate(2).

To a solution of methyl7-bromo-5-(2-hydroxyethyl)thieno[3,2-b]pyridine-3-carboxylate (2, 0.32g, 1.01 mmol) in pyridine (10 mL), acetic anhydride (0.115 mL, 1.22mmol) is added to the reaction mixture. The reaction mixture is stirredat room temperature for 16 h. After completion of reaction as confirmedon thin layer chromatography and LCMS, reaction mixture is diluted withwater and extracted with ethyl acetate. The organic layer is dried overanhydrous sodium sulfate and concentrated to dryness under reducedpressure. The crude is purified by combi flash (4 g, Redi Sep column)using 50% ethyl acetate in hexanes as eluent to afford methyl5-(2-acetoxyethyl)-7-bromothieno[3,2-b]pyridine-3-carboxylate (3).

Example 2B.10

To a solution of 4-chloro-3-fluorophenol (1, 3.0 g, 20.59 mmol) inacetone (30 mL) iodomethane (5.2 mL, 82.00 mmol) and potassium carbonate(5.6 g, 41.00 mmol) are added at room temperature and reaction mixtureis stirred at 60° C. for 12 h. After completion of reaction as confirmedon thin layer chromatography, reaction mass is evaporated and reactionmixture is diluted with water and extracted with ethyl acetate. Theorganic layer is dried over anhydrous sodium sulphate, filtered andconcentrated to get afford 1-chloro-2-fluoro-4-methoxybenzene (2).

To a solution of 1-chloro-2-fluoro-4-methoxybenzene (2, 1.9 g, 11.84mmol) in tetrahydrofuran (20 mL), lithium di-isopropylamide (2 M intetrahydrofuran) (11.8 mL, 23.75 mmol) is added drop wise at −78° C. andreaction mixture is stirred at same temperature for 1 h. Then Tri-Isopropyl Borate (3.26 mL, 14.16 mmol) is added dropwise at −78° C. Thereaction mixture is stirred for 2 h at room temperature. Aftercompletion reaction, reaction mixture is quenched with saturatedsolution of ammonium chloride and extracted with ethyl acetate. Theorganic layer is dried over anhydrous sodium sulphate, filtered andconcentrated to get crude compound. The crude compound obtained ispurified by combi flash chromatography using 12 gm redisep columneluting with 80% ethyl acetate in hexane to afford of(3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (3).

To a solution of (3-chloro-2-fluoro-6-methoxyphenyl)boronic acid (3,0.35 g, 1.71 mmol) in dichloromethane (5 mL) Boron tribromide (0.324 mL,3.43 mmol) is added drop wise at 0° C. and reaction mixture is stirredat room temperature for 1 h. After completion of reaction as confirmedon thin layer chromatography the reaction mixture is quenched with icecold water. The solid precipitated is filtered and washed with pentaneto afford as (3-chloro-2-fluoro-6-hydroxyphenyl)boronic acid (4).

A suspension of tert-butyl7-bromo-5-methylthieno[3,2-b]pyridine-3-carboxylate (4a, 0.230 g 0.8mmol), (3-chloro-2-fluoro-6-hydroxyphenyl)boronic acid (4, 0.30 g, 1.6mmol) and potassium carbonate (0.334 g, 2.4 mmol) in 1,4-dioxane (2.0mL) and water (0.5 mL) is degassed with argon gas 10 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.03 g, 0.04 mmol) is added to above suspensionand reaction mixture is stirred for 3 h at 90° C. The reaction mixtureis monitored with LCMS and thin layer chromatography reaction mixture.After completion, the reaction mass is filtered through Celite bed andwashed with ethyl acetate. The crude compound obtained is purifiedthrough combi flash chromatography using 4 gm redisep column by elutingwith 90% ethyl acetate in hexane to afford tert-butyl7-(3-chloro-2-fluoro-6-hydroxyphenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(5).

Example 2B.11

To a solution of 2,5-dimethylpyridine (1, 10.0 g, 93.4 mmol) inChloroform (100 mL) is added to metachloroperbenzoic acid (19.3 g, 112.1mmol) at 0° C. under argon atmosphere and mixture is stirred at roomtemperature for 16 h. After completion, the reaction mixture is dilutedwith 10% calcium hydroxide solution and the solution is filtered throughcelite, filtrate is concentrated and dried to afford2,5-dimethylpyridine 1-oxide (2).

To a solution of 2,5-dimethylpyridine 1-oxide (2, 10.0 g, 81.3 mmol) indichloromethane (100 ml) is added to Trimethylsilylcyanide (11.2 g, 89.4mmol) at 0° C. under argon atmosphere and stirred at room temperaturefor 30 minute, diethylcarbamic chloride (2a, 11.3 mL, 89.4 mmol) isadded and stirring continued at room temperature for 24 h. Aftercompletion, the reaction mixture is quenched with 10% potassiumcarbonate solution and extracted with ethyl acetate. Organic layer isdried over anhydrous sodium sulfate and concentrated to dryness underreduced pressure. The crude product is purified by column chromatographyusing silica (100-200 mesh) using 30-40% ethyl acetate in hexanes aseluent. The desired fractions are concentrated under reduced pressure toafford 3,6-dimethylpicolinonitrile (3).

To a solution of 3,6-dimethylpicolinonitrile (3, 7.00 g, 46.9 mmol) inChloroform (70 mL) is added to metachloroperbenzoic acid (8.75 g, 56.6mmol) at 0° C. under argon atmosphere and stirring continued at roomtemperature for 16 h. After completion, the reaction mixture is dilutedwith 10% calcium hydroxide solution and filtered through celite,filtrate is concentrated and dried to afford2-cyano-3,6-dimethylpyridine 1-oxide (4).

A solution of 2-cyano-3,6-dimethylpyridine 1-oxide (4, 7.0 g, 46.9 mmol)in phosphoryl chloride (50 mL) is stirred at 90° C. for 4 h. Aftercompletion, the reaction mixture is concentrated and purified by columnchromatography using silica (100-200 mesh) using 20-30% ethyl acetate inhexanes as eluent. The desired fractions are concentrated under reducedpressure to afford 4-chloro-3,6-dimethylpicolinonitrile (5).

A solution of 4-chloro-3,6-dimethylpicolinonitrile (5, 4.0 g, 24.0 mmol)in ethanol (20 mL) and 10% Potassium hydroxide solution (20 mL) isstirred at 100° C. for 16 h. After completion, the reaction mixture iscooled and acidified with 2M hydrochloric acid solution up to pH 5 andextracted with ethyl acetate. Organic layer is dried over anhydroussodium sulfate, filtered and concentrated to dryness under reducedpressure. To afford 4-chloro-3,6-dimethylpicolinic acid (6).

To a solution of 4-chloro-3,6-dimethylpicolinic acid (6, 1.50 g, 8.10mmol) in tert-butyl alcohol (9.0 ml) is added di-tert-butyl dicarbanate(0.75 mL, 3.56 mmol) and 4-dimethylamino pyridine (1.48 g, 12.1 mmol) at0° C. under argon atmosphere and stirred at 90° C. for 4 h. Aftercompletion, the reaction mixture is concentrated under reduced pressure.The crude compound is purified by flash column chromatography using20-30% ethyl acetate in hexane to afford tert-butyl4-chloro-3,6-dimethylpicolinate (7).

Example 2B.12

To a stirred solution of thieno [3,2-b]pyridin-7-ol (1, 5.0 g, 33.07mmol) in 1,2-dichloroethane (50 mL) is added phosphorous oxybromide(143.21 g, 496.09 mmol) portionwise at room temperature and the mixtureis stirred at 70° C. for 10 h. The reaction mixture is cooled at 0° C.,basified with 10% aqueous solution of sodium hydroxide and extractedwith dichloromethane. The organic layer is washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated to dryness underreduced pressure to afford 7-bromothieno[3,2-b]pyridine (2).

To a stirred solution of 7-bromothieno[3,2-b]pyridine (2, 4.0 g, 18.78mmol) in dry tetrahydrofuran (40 mL) is added lithium diisopropylamidesolution (2.0 M in hexanes, 26.30 mL, 53.60 mmol) drop wise at −78° C.and the mixture is stirred at same temperature for 1 h. Carbon dioxidegas is purged through the reaction mass for 15 min and the reactionmixture is allowed to warm up to room temperature over 4 h. The reactionis quenched with aqueous ammonium chloride solution, diluted with waterand extracted with ethyl acetate. The organic layer is washed withsaturated brine, dried over anhydrous sodium sulphate, filtered andconcentrated to afford 7-bromothieno[3,2-b]pyridine-2-carboxylic acid(3).

Example 2B.12

To a stirred solution of (4-methoxyphenyl)methanethiol (12.3 g, 87.77mmol) in N,N-dimethylformamide (150 mL) is added sodium hydride (4.60 g,119.69 mmol) portion wise at 0° C. After 10 min,1-bromo-2-fluoro-4-methylbenzene (1, 15.0 g, 79.79 mmol) is added andthe reaction is stirred at room temperature for 2 h. After completion,the reaction is poured into ice water and extracted with ethyl acetate.The organic layer is washed with water, brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to get the crude.The crude product is purified by Combiflash (40 g, RediSep column) using0-5% ethyl acetate in hexanes as eluent. The desired fractions areconcentrated under reduced pressure to afford(2-bromo-5-methylphenyl)(4-methoxybenzyl)sulfane (2).

To a solution of (2-bromo-5-methylphenyl)(4-methoxybenzyl)sulfane (2,18.0 g, 55.90 mmol) in dichloromethane (140 mL) is added a mixture oftrifluoroacetic acid (20 mL) and triflic acid (5 mL) in dichloromethane(40 mL) at 0° C. drop wise and the reaction mixture is stirred at roomtemperature for 2 h. After completion, the reaction is poured intoice-water and extracted with dichloromethane. The organic layer iswashed with water, brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to get the crude product2-bromo-5-methylbenzenethiol (3).

To a solution 2-bromo-5-methylbenzenethiol (3, 4.7 g, 23.27 mmol) inacetone (47.0 mL) is added potassium carbonate (16.0 g, 116.35 mmol) atroom temperature and the mixture is stirred for 10 min.3-Bromo-2-oxopropanoic acid (3a, 11.6 g, 69.80 mmol) is added to thereaction mixture and stirred for 5 h at room temperature. Aftercompletion, the acetone is evaporated under reduced pressure; theresidue is diluted with water and extracted with ethyl acetate. Theorganic layer is washed with water, brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to get3-((2-bromo-5-methylphenyl)thio)-2-oxopropanoic acid (4).

To a solution of 3-((2-bromo-5-methylphenyl)thio)-2-oxopropanoic acid(4, 4.0 g, 13.89 mmol) in dichloromethane (40.0 mL) is added sulfuricacid (10.0 mL) and the reaction mixture is stirred at room temperaturefor 5 h. After completion, the reaction mixture is poured into icewater, extracted with dichloromethane. The organic layer is washed withwater, brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure to get 7-bromo-4-methylbenzo[b]thiophene-3-carboxylicacid (5).

To a solution 7-bromo-4-methylbenzo[b]thiophene-3-carboxylic acid (5,3.0 g, 11.11 mmol) in N,N-dimethylformamide (30.0 mL) is added potassiumcarbonate (4.6 g, 33.33 mmol) and iodomethane (1.4 mL, 22.22 mmol) at 0°C. and the reaction mixture is stirred at room temperature for 4 h.After completion, the reaction mass is poured into water and extractedwith ethyl acetate. The organic layer is washed with water, brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure;the crude product is purified by flash column chromatography using 5%ethyl acetate in hexanes as eluent. The desired fractions areconcentrated under reduced pressure to afford methyl7-bromo-4-methylbenzo[b]thiophene-3-carboxylate (6).

Example 2B.13

To a solution of tert-butyl4-bromo-7-chlorobenzo[b]thiophene-3-carboxylate (1, 0.7 g, 2.01 mmol) inN,N-dimethylformamide (2 mL), copper(I) cyanide (0.180 g, 2.01 mmol) isadded. This reaction mixture is heated at 90° C. for 2 h. After thistime, the reaction mixture is filtered with Celite and washed with ethylacetate. The filtrate is washed with water and then brine solution,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to obtain the crude product. This is purified by columnchromatography using silica gel (100-200 mesh) and 30-50% ethyl acetatein hexane as eluent. The desired fractions are concentrated underreduced pressure to afford tert-butyl7-chloro-4-cyanobenzo[b]thiophene-3-carboxylate (2).

Example 2B.14

A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1, 0.41 g, 2.84 mmol)and diethoxymethoxyethane (50.0 mL) is stirred and heated at 90° C. for2 h in a closed vessel. Methyl 3-aminothiophene-2-carboxylatehydrochloride (1a, 0.5 g, 2.58 mmol) is added portion wise at 90° C.under argon atmosphere and continued heating at 90° C. for 12 h. Aftercompletion, the reaction mass is cooled to room temperature, added waterand extracted with ethyl acetate. The organic layer is dried overanhydrous sodium sulfate, filtered and concentrated under vacuo to getcrude. The crude is triturated with diethyl ether to afford methyl3-((1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethyl)amino)thiophene-2-carboxylate(2).

A solution of methyl3-((1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethyl)amino)thiophene-2-carboxylate(2, 0.200 g, 0.61 mmol) in N-methyl pyrrolidone (15 mL) is heated inmicrowave at 200° C. for 30 min. After completion, the reaction mass iscooled to room temperature, filtered and the crude solid is purified byprep-HPLC to afford methyl4-hydroxy-2-methylthieno[3,4-b]pyridine-7-carboxylate (3).

Example 2B.15

To a stirred solution of 7-chloro-3-methylthieno[3,2-b]pyridine (1, 1.0g, 5.44 mmol) in ethyleacetate (10 mL) are added1-bromopyrrolidine-2,5-dione (1a, 1.93 g, 10.8 mmol) andazobisisobutyronitrile (0.088 g, 0.540 mmol) at room temperature. Thereaction is stirred at 60° C. for 4 h. After completion, the reactionmixture is quenched with water and extracted with ethyl acetate. Theorganic layer is washed with brine solution, dried over anhydrous sodiumsulfate, filtered and concentrated to dryness under reduced pressure.The crude product is purified by Combiflash (12 g, RediSep column) using1-5% ethylacetate in hexanes as eluent to afford3-(bromomethyl)-7-chlorothieno[3,2-b]pyridine (2).

To a solution of 3-(bromomethyl)-7-chlorothieno[3,2-b]pyridine (2, 1.50g, 5.70 mmol) in N,N-dimethylformamide (15 mL) is added sodium cyanide(0.561 g, 11.40 mmol) and the mixture is stirred at room temperature for3 h. After completion, the reaction is quenched with ice cold water andextracted with ethyl acetate. The organic layer is washed with coldwater, dried over anhydrous sodium sulfate, filtered and concentrated todryness under reduced pressure to afford2-(7-chlorothieno[3,2-b]pyridin-3-yl)acetonitrile (3).

To a solution of 2-(7-chlorothieno[3,2-b]pyridin-3-yl)acetonitrile (3,1.10 g, 5.20 mmol) in a mixture of ethanol and water (1:1, (20 mL) isadded potassium hydroxide (2.96 g, 52.8 mmol) and the mixture is stirredat 60° C. for 10 h. After completion, the reaction mixture isconcentrated and extracted with diethyl ether. The aqueous layer isacidified with 1 N aqueous hydrochloric acid solution, and extractedwith ethyl acetate. The organic layer is washed with saturated brinesolution, dried over anhydrous sodium sulphate, filtered andconcentrated to afford 2-(7-chlorothieno[3,2-b]pyridin-3-yl)acetic acid(4).

Example 2B.16

To a solution of 1H-pyrrolo[3,2-b]pyridine (1, 2.5 g, 21 mmol) in DCM(75 mL) at 0° C. is slowly added m-CPBA (5.69 g, 25.4 mmol). The mixtureis stirred from 0° C. to rt. After 16 h the reaction is complete asjudged by TLC (SiO₂, 10% MeOH/DCM). The mixture is concentrated and theresidue purified by column chromatography (SiO₂, 0-20% MeOH/DCM). Theproduct is isolated as a mixture with m-CBA (ratio ca. 1:0.7 by ¹H-NMR).The so-obtained material 1H-pyrrolo[3,2-b]pyridine 4-oxide (2).

1H-pyrrolo[3,2-b]pyridine 4-oxide (2, 3.64 g) in POCl₃ (30 mL, 50 g,0.32 mol) are refluxed overnight under argon (oil-bath, 130° C.). Thenthe mixture is carefully transferred into an Erlenmeyer flask withcrushed ice with stirring. The mixture is then basified with NaOH (aq,12.5%) to pH ca. 8, and the precipitated material is collected byfiltration. The aq. phase is extracted (3× EtOAc), and the combinedorganic phases are dried (Na₂SO₄), filtered and concentrated. Theprecipitated and extracted material are combined, dissolved in DCM andwashed with NaHCO₃ (aq). The organic phase is dried (Na₂SO₄), filteredand concentrated to afford 7-chloro-1H-pyrrolo[3,2-b]pyridine (3).

The reaction is run in two batches (0.80 g of (3) per batch), and thetwo batches are combined for purification purposes. To a solution of7-chloro-1H-pyrrolo[3,2-b]pyridine (3, 0.80 g, 5.2 mmol) in 1,4-dioxane(14 mL) and water (3.5 mL) are added (5-chloro-2-hydroxyphenyl)boronicacid (3a, 1.4 g, 8.1 mmol) and potassium carbonate (2.2 g, 16 mmol) andthe mixture is degassed by bubbling argon through it for 5 min.Pd(PPh₃)₄ (0.61 g, 0.53 mmol) is added, and the mixture is degassed foranother 5 min, then placed in a preheated heating block (100° C.) andstirred for 20 h. Then the mixture is cooled down to room temperature.The two batches are combined, diluted with water, extracted with EtOAc.The organic phase is dried (Na₂SO₄), filtered, and concentrated.Purification by column chromatography (SiO₂, 0-20% MeOH/DCM) to afford4-chloro-2-(1H-pyrrolo[3,2-b]pyridin-7-yl)phenol (4).

To a solution of 4-chloro-2-(1H-pyrrolo[3,2-b]pyridin-7-yl)phenol (4, 37mg, 0.15 mmol) in DMF (0.7 mL) at 0° C. are added imidazole (23 mg, 0.34mmol) and tert-butyl-chloro-diphenyl-silane (0.05 mL, 0.05 g, 0.2 mmol),and the mixture is stirred at rt. After 3 h the mixture is diluted withwater and EtOAc, and the aq. phase is extracted (3× EtOAc). The combinedorganic phases are dried (Na₂SO₄), filtered and concentrated.Purification by column chromatography (SiO₂, 0-40% EtOAc/hexane) toafford7-(2-((tert-butyldiphenylsilyl)oxy)-5-chlorophenyl)-1H-pyrrolo[3,2-b]pyridine(5).

To a solution of7-(2-((tert-butyldiphenylsilyl)oxy)-5-chlorophenyl)-1H-pyrrolo[3,2-b]pyridine(5; 1.08 g, 2.24 mmol) in THF (20 mL) at 0° C. is addedN-Iodosuccinimide (503 mg, 2.24 mmol) and the mixture is stirred for 10min. Then the reaction is diluted with EtOAc, quenched with Na₂S₂O₃ (aq)and water, and extracted (2× EtOAc). The combined organic phases aredried, filtered and concentrated. Purification by column chromatography(SiO₂, 0-40% EtOAc/hexane) afforded to afford7-(2-((tert-butyldiphenylsilyl)oxy)-5-chlorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine(6).

To a solution of7-(2-((tert-butyldiphenylsilyl)oxy)-5-chlorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine(6, 990 mg, 1.63 mmol) in MeCN (11 mL) at 0° C. are added triethylamine(0.45 mL, 0.33 g, 3.2 mmol), di-tert-butyl dicarbonate (531 mg, 2.43mmol) in 2 mL MeCN and 4-dimethylaminopyridine (40 mg, 0.33 mmol) andthe mixture is stirred at rt. After 1 h water is added, and the mixtureis extracted with DCM (3×). The combined organic phases are dried(Na₂SO₄), filtered and concentrated. Purification by columnchromatography (SiO₂, 0-20% EtOAc/hexane) to afford tert-butyl7-(2-((tert-butyldiphenylsilyl)oxy)-5-chlorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(7).

To a solution of tert-butyl7-(2-((tert-butyldiphenylsilyl)oxy)-5-chlorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(7, 1.06 g, 1.49 mmol) in methanol (11 mL) and DMF (4 mL) are addedtriethylamine (0.43 mL, 0.31 g, 3.1 mmol) and (Ph₃P)₂PdCl₂ (105 mg,0.149 mmol). Then the mixture is stirred at 50° C. under a COatmosphere. After 18 h the mixture is concentrated and purified bycolumn chromatography (SiO₂, 0-50% EtOAc/hexane) to afford1-(tert-butyl) 3-methyl7-(2-((tert-butyldiphenylsilyl)oxy)-5-chlorophenyl)-1H-pyrrolo[3,2-b]pyridine-1,3-dicarboxylate(8).

Example 2B.17

To a solution of 3-bromo-7-chlorothieno[3,2-b]pyridine (4, 0.30 g, 1.21mmol), and ethyl 2-bromo-2,2-difluoroacetate (4a, 0.73 g, 3.62 mmol) indimethylsulfoxide (12.0 mL), cupper powder (0.11 g, 1.81 mmol) is addedat room temperature and the mixture is heated at 60° C. for 16 h. Aftercompletion, reaction mass is diluted with ethyl acetate and filteredthrough Celite. The filterate is washed with water and brine solution,dried over sodium sulfate filtered and concentrated. The crude ispurified by flash column chromatography using silica gel (100-200 mesh)and 20-30% ethyl acetate in hexane as eluent. The desired fractions areconcentrated under reduced pressure to afford ethyl2-(7-chlorothieno[3,2-b]pyridin-3-yl)-2,2-difluoroacetate (5).

Example 2B.18

To a solution of N,N,N′,N′-tetramethylethylenediamine (11.69 g, 100.42mmol) in tetrahydrofuran (100 mL), n-butyllithium (1.3 M in hexane, 71.1mL, 92.43 mmol) is added at −78° C., then6,7-dihydro-5H-cyclopenta[b]pyridine (1, 10.0 g, 84.03 mmol) is addeddropwise and the mixture is stirred at −78° C. for 45 min. Then, asolution of dimethyl carbonate (1a, 8.31 g, 92.43 mmol) intetrahydrofuran (10 mL) is added drop wise and the mixture is allowed toroom temperature over an 1 h. The reaction mixture is quenched withsaturated ammonium chloride solution and extracted with ethyl acetate.The combined organic layer is dried over anhydrous sodium sulphate,filtered and concentrated. The crude is purified by columnchromatography using silica gel (100-200 mesh) and 0-25% ethyl acetatein hexane as eluent to afford methyl6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate (2).

To a solution of methyl6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate (2, 2.5 g, 14.12mmol) in dichloromethane (30 mL), 3-chloroperbenzoic acid (4.85 g, 28.24mL) is added at 0° C. and the mixture is stirred at the same temperaturefor 30 min. After completion, the reaction mixture is quenched withsaturated sodium bicarbonate solution (10 mL) and extracted withdichloromethane. The combined organic layer is washed brine, dried overanhydrous sodium sulphate, filtered and concentrated. The crude ispurified by column chromatography using silica gel (100-200 mesh) and0-10% methanol in dichloromethane as eluent. The desired fractions areconcentrated under reduced pressure to afford7-(methoxycarbonyl)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (3).

To a solution of7-(methoxycarbonyl)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (3, 1.5g, 7.77 mmol) in acetonitrile (25 mL), lithium bromide (0.67 g, 7.77mmol) and phosphorus bromide (22.3 g, 77.72 mmol) are added and thereaction mixture is heated at 80° C. for 24 h. After completion, thereaction mixture is cooled to 0° C., quenched with saturated sodiumbicarbonate solution (50 mL) and extracted with ethyl acetate. Thecombined organic layer is dried over anhydrous sodium sulphate, filteredand concentrated. The crude is purified by column chromatography usingsilica gel (100-200 mesh) and 0-25% ethyl acetate in hexane to affordmethyl 4-bromo-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate (4).

Example 2B.19

To a solution of 7-bromothieno[3,2-b]pyridine-3-carbaldehyde (1, 36 mg,0.148 mmol) in DCM (1 mL) in an oven-dried screw capped vial is equippedwith a stir bar. To the mixture is added ethoxyethane trifluoroborane(0.02 mL, 0.163 mmol) with constant stirring at room tem added slowly.Then 1,2-bis((trimethylsilyl)oxy)cyclobut-1-ene (1a, 0.06 mL, 0.222mmol) is added dropwise and the clear yellow mixture continued to stirat room temperature for 40 min. Water (0.030 mL) is added followed byethoxyethane; trifluoroborane (0.27 mL, 2.22 mmol) and the reaction isallowed to stir at room temperature overnight. No conversion to pinacolrearrangement product observed so water and DCM added and the aqueousphase extracted with dichloromethane three times. The combined organicmaterial is washed with brine and dried over magnesium sulfate. Thesolids are filtered and solvent removed in vacuo to afford a crudeyellow residue. Aqueous layer is concentrated in vacuum. Both aqueousand organic layer combined and is taken up in TFA (3.5 mL, 0.1480 mmol)and placed in a vial that is sealed and stirred in a heating block at70° C. for 3 h. The reaction is cooled to room temperature and solventremoved in vacuo. Preparatory HPLC (water with 0.1% TFA) afforded theproduct2-(7-bromothieno[3,2-b]pyridin-3-yl)-3-hydroxycyclopent-2-en-1-one (2).

Example 2B.20

To a stirred solution of methyl7-chlorothieno[3,2-b]pyridine-3-carboxylate (1, 15.0 g, 65.88 mmol) inmethanol, tetrahydrofuran and water (2:1:1, 225 mL) is added lithiumhydroxide (13.82 g, 329.43 mmol) at 0° C. and reaction mixture isstirred at room temperature for 16 h. After completion, the solvents areconcentrated under reduced pressure and the aqueous layer is acidifiedwith 1 N aqueous hydrochloric acid solution up to pH-3. Solidprecipitate obtained is filtered and washed with n-pentane to afford7-chlorothieno[3,2-b]pyridine-3-carboxylic acid (2).

To a solution of 7-chlorothieno[3,2-b]pyridine-3-carboxylic acid (2,12.20 g, 57.10 mmol) in N,N-dimethylformamide (50 mL) is added1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (32.5 g, 85.65 mmol) and reaction mixture isstirred for 10 min. The reaction mixture is then cooled to 0° C. andN,N-diisopropylethylamine (29.841 mL, 171.316 mmol) and ammoniumchloride (15.2 g, 285.52 mmol) are added and reaction mixture is allowedto warm to room temperature and stirred for 16 h. After completion, thereaction is quenched with ice cold water and extracted with ethylacetate. The organic layer is washed with cold water, dried overanhydrous sodium sulfate, filtered and concentrated to dryness underreduced pressure. The crude product is triturated with pentane and driedto afford 7-chlorothieno[3,2-b]pyridine-3-carboxamide (3).

To a solution of 7-chlorothieno[3,2-b]pyridine-3-carboxamide (3, 10.0 g,51.37 mmol) in N,N-dimethylformamide (100 mL) at 0° C. is addedphosphorus oxytrichloride (48.0 mL, 513.76 mmol). The reaction isallowed to warm up to room temperature and stirred for 16 h. Aftercompletion, reaction mixture concentrated to dryness under reducedpressure. The reaction mixture is basified with saturated sodiumbicarbonate solution up to pH-8 and extracted with ethyl acetate. Theorganic layer is washed with brine solution, dried over anhydrous sodiumsulfate, filtered and concentrated to dryness under reduced pressure.The crude product is purified by Combiflash (40 g, RediSep column) using0-20% ethyl acetate in hexanes as eluent. The desired fractions areconcentrated under reduced pressure to afford7-chlorothieno[3,2-b]pyridine-3-carbonitrile (4).

To a solution of 7-chlorothieno[3,2-b]pyridine-3-carbonitrile (4, 8.0 g,41.10 mmol), and (5-chloro-2-hydroxyphenyl)boronic acid (4a, 14.1 g,82.20 mmol) in 1,4-dioxane (120.0 mL) is added 2 M solution of potassiumcarbonate (14.2 g, 102.7 mmol) reaction mixture is degassed with argongas for 10 min. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II)dichloride (3.0 g, 4.11 mmol) is then added to reaction mixture andreaction mixture is stirred at 110° C. for 2 h. After completion,reaction mixture is cooled to room temperature, diluted with water andextracted with ethyl acetate. The organic layer is washed with brinesolution, dried over anhydrous sodium sulfate, filtered and concentratedto dryness under reduced pressure. The crude product is purified bycolumn chromatography using silica gel (100-200 mesh) and 0-50% ethylacetate in hexanes as eluent. The desired fractions are concentratedunder reduced pressure to afford7-(5-chloro-2-hydroxyphenyl)thieno[3,2-b]pyridine-3-carbonitrile (5).

To a solution of7-(5-chloro-2-hydroxyphenyl)thieno[3,2-b]pyridine-3-carbonitrile (5, 5.1g, 17.78 mmol) in N,N-dimethylformamide (50.0 mL) is added sodium azide(5.8 g, 88.93 mmol) at room temperature and the reaction mixture isheated to 110° C. for 36 h. After completion, reaction mixture isconcentrated to dryness under reduced pressure. The crude productobtained is triturated with n-pentane to afford2-(3-(1H-tetrazol-5-yl)thieno[3,2-b]pyridin-7-yl)-4-chlorophenol (6).

Example 2C. General Coupling Methods

To a solution2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(6, 0.20 g, 0.79 mmol) in N,N-dimethylformamide (5 mL), potassiumcarbonate (0.33 g, 2.37 mmol) is added at room temperature. After 10min, 2-bromo-1-(2-bromoethoxy)-4-chlorobenzene (9, 0.25 g, 0.79 mmol) isadded and stirred for 16 h at room temperature. After completion, thereaction mixture is poured into water and extracted with ethyl acetate.Combined organic layer is washed with water, brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to get crude; thecrude compound is purified by flash column chromatography (using 10-70%ethyl acetate in hexanes) to afford3-(2-(2-bromo-4-chloro-phenoxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(10).

Example 2D. Post Coupling Modification Methods Example 2D.1

A solution of3-(2-(2-bromo-4-chlorophenoxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(10, 1.8 g, 3.71 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (11, 1.13 g,4.45 mmol) and potassium acetate (0.73 g, 7.42 mmol) in 1,4-dioxane (35mL) is degassed using argon gas for 10 min.1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.217 g,0.296 mmol) is added and the reaction mixture is degassed for another 10min. The reaction mixture is heated and stirred at 90° C. for 6 h. Aftercompletion, the reaction mixture is diluted with water and extractedwith ethyl acetate. The organic layer is dried over anhydrous sodiumsulfate, filtered and concentrated to dryness under reduced pressure.The crude compound is purified by flash column chromatography 40% ethylacetate in hexanes as eluent to afford3-(2-(4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(12).

To a solution methyl 3-bromo-2-iodobenzoate (13, 2.0 g, 5.88 mmol)N,N-dimethylformamide (20 mL), copper(I) cyanide (0.58 g, 6.47 mmol) isadded and heated at 60° C. for 4 h. After completion, the reaction massis diluted with water (100 mL) and extracted with ethyl acetate.Combined organic layer are washed with water, brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure to getcrude. The crude compound is purified by flash column chromatography(using 0-10% ethyl acetate in hexane) to afford methyl3-bromo-2-cyanobenzoate (14).

To a solution of3-(2-(4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(12, 0.40 g, 0.75 mmol) and methyl 3-bromo-2-cyanobenzoate (14, 0.215 g,0.90 mmol) in 1,4-dioxane (8 mL) and water (2 mL), potassium carbonate(0.313 g, 2.25 mmol) is added at room temperature. The reaction mass isdegassed by purging argon gas through the reaction mass for 10 min.1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.055 g,0.075 mmol) is added under argon atmosphere, heated and stirred thereaction mixture at 90° C. for 3 h. After completion, the reaction massis diluted with water, extracted with ethyl acetate; combined organiclayer is washed with water, brine and dried over anhydrous sodiumsulfate and concentrated under reduced pressure to get crude. The crudecompound is purified by flash column chromatography (using 0-50% ethylacetate in hexane) to afford methyl5′-chloro-2-cyano-2′-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)-[1,1′-biphenyl]-3-carboxylate(15).

Example 2D.2

To a stirred solution of methyl5-chloro-7-[5-chloro-2-[2-[5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3-yl]ethoxy]phenyl]thieno[3,2-b]pyridine-3-carboxylate(0.050 g, 0.079 mmol) in N-methyl-2-pyrrolidone and water (9:1, 2 mL) ina microwave vial, zinc cyanide (0.011 g, 0.095 mmol) and zinc dust(0.030 mg, 0.034 mmol) are added and the mixture is degassed with argonfor 30 min. After adding 1,1′-bis(diphenylphosphino)ferrocene (0.0131 g,0.023 mmol) and tris(dibenzylideneacetone)dipalladium(0) (10.8 mg, 0.012mmol), the vial is sealed and then placed in a preheated heating blockat 80° C. for 30 min. After completion of the reaction, the reactionmixture loaded on the Isco silica column. Purification by columnchromatography eluting with 0 to 5% methanol/dichloromethane to affordmethyl7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-cyanothieno[3,2-b]pyridine-3-carboxylate(2).

To a solution of methyl7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-cyanothieno[3,2-b]pyridine-3-carboxylate(2, 25.0 mg, 0.040 mmol) in 1,2-dichloroethane (2 mL), trimethyltinhydroxide (0.029 g, 0.160 mmol) is added at room temperature. Thereaction mixture is heated at 90° C. for 16 h. After completion of thereaction, the organic solvent is evaporated and the crude is dilutedwith 50% dimethyl sulfoxide/methanol. The crude product is purified byprep-HPLC to afford5-carbamoyl-7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (Cpd. No. 445F).

Example 2D.3

To a solution of methyl7-(2-(2-(5-bromo-6-iodo-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(5, 0.20 g, 0.256 mmol) in N,N-dimethylformamide is added copper(I)cyanide (0.069 g, 0.770 mmol) and stirred at 85° C. for 2 h. Aftercompletion, the reaction mixture is cooled to room temperature andpoured into ice-water. The precipitate formed is collected by filtrationand dried. The solid is dissolved in 10% methanol in dichloromethane andpassed through Celite bed. The filtrate is concentrated under reducedpressure to afford methyl7-(5-chloro-2-(2-(5,6-dicyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(6).

Example 2D.3

To a solution of tert-butyl7-(2-(2-(6-bromo-5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(1, 0.20 g, 0.273 mmol) in N-Methyl-2-pyrrolidone (5.0 mL) is added1-methylpiperazine (1a, 0.06 mL, 0.546 mmol) and the reaction mixture isdegassed by argon for 10 min. Then copper(I) iodide (0.005 g, 0.027mmol) and 1,10-phenanthroline (0.009 g, 0.054 mmol) is added andreaction mixture is heated at 150° C. for 6 h. After completion reactionmixture is diluted with water and extracted with ethyl acetate. Theorganic layer is dried over anhydrous sodium sulphate, filtered andconcentrated to get crude compound. Crude compound obtained is purifiedby column chromatography using silica gel (100-200 mesh) and 3-4%methanol in dichloromethane to afford tert-butyl7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(2).

Example 2D.4

To a solution of tert-butyl7-(2-(2-(6-bromo-5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(1, 50 mg, 0.0681 mmol) and 3-fluoro-2-((tributylstannyl)methyl)pyridine(1a, 190 mg, 0.476 mmol) in N,N-dimethylformamide (2 mL), is addedcopper(II) oxide (11 mg, 0.136 mmol) at room temperature. The reactionmixture is purged with argon gas for 5 min, addedbis(triphenylphosphine)palladium(II) dichloride (9.6 mg, 0.0136 mmol)and the vessel is then sealed, microwaved for 1 h at 150′° C. Aftercompletion, the reaction mixture is then directly loaded on an Iscoloading column. Purified by column chromatography using 5 to 80% ethylacetate in hexane as eluent and product eluted around 60%ethylacetate/hexane. The desired fractions are concentrated underreduced pressure to afford tert-butyl7-(5-chloro-2-(2-(5-cyano-6-((3-fluoropyridin-2-yl)methyl)-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(2).

Compounds made using one or more of the general methods described aboveare shown in Table 2. Where provided, characterization data is to theright of the compounds.

TABLE 2 7-CF3-Thienylpyridine and Derivative Compounds CompoundCharacterization 51

MS (ESI) m/z 528.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.931 (s,1H), 8.359 (s, 1H), 8.194 (s, 1H), 7.8409 (d, J = 11.6 Hz, 2H), 7.528(d, J = 7.6 Hz, 1H), 7.412 (m, 2H), 7.278 (d, J = 2.6 Hz, 1H), 7.212 (d,J = 8.8 Hz, 1H), 4.359 (s, 4H), 2.208 (s, 3H) 58

MS (ESI) m/z 553.34 [M + 1]+; UPLC: 98.94%; 1H NMR (400 MHz, DMSO-d6) δ8.44 (d, J = 3.96, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 7.43 (dd, J = 2.48,8.88 Hz, 1H), 7.23-7.18 (m, 3H), 4.33 (m, 4H), 4.03 (s, 1H), 2.09 (s,3H) 59

MS (ESI) m/z 578.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H),8.28 (s, 1H), 7.84-7.81 (m, 2H), 7.6-7.2 (m, 6H), 4.37 (s, 4H), 2.21 (s,3H) 60

MS (ESI) m/z 527.02 [M + 1]−. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (bs, 1H),8.37 (s, 1H), 8.19 (s, 1H), 7.98 (bs, 1H), 7.61 (bs, 1H), 7.48 (d, J =8.68 Hz, 1H), 7.42 (s, 1H), 7.26 (d, J = 8.92 Hz, 1H), 4.39 (s, 4H),2.20 (s, 3H) 61

MS (ESI) m/z 585.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H),8.84 (d, J = 4.76, 1H), 8.37 (d, J = 0.96 Hz, 1H), 8.26 (s, 1H), 8.00(s, 1H), 7.59 (dd, J = 2.64, 8.92 Hz, 1H), 7.48 (d, J = 4.76 Hz, 1H),7.43 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 8.96, 1H), 4.42-4.23 (m, 4H),1.74 (s, 3H) 65

MS (ESI) m/z 621.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.7935 (d, J =4.8 Hz, 1H), 8.568 (s, 1H), 8.338 (s, 1H), 8.236 (s, 1H), 7.610 (dd, J =8.8 Hz, 1H), 7.487 (d, J = 4.8 Hz, 1H), 7.441 (d, J = 2.8 Hz, 1H), 7.372(d, J = 9 Hz, 1H),6.687-6.429 (m, 1H), 4.431-4.355 (m, 4H) 120

MS (ESI) m/z 579.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.48 Hz, 1H), 8.59 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.69 (d, J = 6.04 Hz, 2H), 7.56 (d, J = 4.48 Hz, 1H), 4.88 (s,2H), 2.10 (s, 3H) 121

MS (ESI) m/z 599.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H),8.36 (s, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.60-7.57 (dd, J = 2.52 Hz,1H), 7.41 (s, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.40 (t, J = 4.6 Hz, J =4.48 Hz, 2H), 4.25 (t, J = 4.04 Hz, J = 5.0 Hz, 2H), 2.69 (s, 3H), 1.81(s, 3H) 122

MS (ESI) m/z 601.98 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.93 (bs,1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 7.51 (dd, J = 8.88, 2.6Hz, 1H), 7.29-7.22 (m, 4H), 4.35 (t, J = 4.4 Hz, 2H), 4.24 (t, J = 4.84Hz, 2H), 1.77 (s, 3H) 145

MS (ESI) m/z 524.41 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H),8.37 (s, 1H), 8.19 (s, 1H), 7.8480-7.726 (m, 3H), 7.4848-7.454 (m, 3H),7.36 (s, 1H), 6.43 (d, J = 15.68 Hz, 1H), 6.15 (d, J = 15.68 Hz, 1H),4.83 (d, J = 3.4 Hz, 2H), 2.56 (s, 3H) 146

MS (ESI) m/z 526.46 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (bs,1H), 8.35 (d, J = 1.36 Hz, 1H), 8.177 (s, 1H), 7.767 (s, 1H), 7.744 (s,1H), 7.58-7.557 (m, 1H), 7.467-7.382 (m, 3H), 7.229 (d, J = 6.4 Hz, 1H),3.933 (t, J = 7.04 Hz, 2H), 2.611 (t, J = 8.44 Hz, 2H), 2.447 (s, 3H),1.768 (m, 2H) 156

MS (ESI) m/z 552.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.92 (bs,1H), 8.34 (s, 1H), 8.18 (s, 1H), 7.83 (dd, J = 7.64, 1.0 Hz, 1H),7.44-7.34 (m, 3H), 7.16-7.14 (m, 2H), 4.31 (bs, 4H), 3.73 (s, 1H), 1.98(s, 3H) 158

MS (ESI) m/z 572.49 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.15 (bs,1H), 8.36 (s, 1H), 8.21 (s, 1H), 7.63 (s, 1H), 7.58 (d, J = 8 Hz, 1H),7.51 (d, J = 7.6 Hz, 1H), 7.429-7.401 (dd, J = 2.4 Hz, J′ = 8.72 Hz,1H), 7.33 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 4.37 (s, 4H),2.25 (s, 3H) 159

MS (ESI) m/z 538 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H),8.29 (s, 1H), 8.01 (s, 1H), 7.59 (bs, 1H), 7.38-7.36 (m, 1H), 7.32- 7.30(m, 1H), 7.20 (d, J = 2.56 Hz, 2H), 7.16 (d, J = 8.76 Hz, 1H), 4.26 (s,4H), 3.8 (s, 1H) 162

MS (ESI) m/z 515.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J =5.04 Hz, 1H), 8.43 (d, J = 1.08 Hz, 1H), 8.27 (s, 1H), 8.23 (s, 1H),8.03 (s, 1H), 7.67-7.65 (dd, J = 1.52, 4.96 Hz, 1H), 7.49 (d, J = 2.72Hz, 1H), 7.47 (s, 1H), 7.25 (d, J = 9.28 Hz, 1H), 4.40-4.37 (m, 4H) 164

MS (ESI) m/z 571 [M + 1]; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.43(d, J = 16.6 Hz, 2H), 8.11 (s, 1H), 7.79 (bs, 1H), 7.60 (s, 1H), 7.46(m, 2H), 7.35 (m, 1H), 4.40 (s, 2H), 4.20 (s, 2H), 3.89 (s, 1H) 168

MS (ESI) m/z 553.20 [M + 1]+. UPLC: 98.95%; 1H NMR (400 MHz, DMSO-d6) δ13.65 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 8.08 (d, J = 7.68 1H),7.78-7.76 (t, J = 7.76 Hz, 1H), 7.61 (d, J = 7.24 Hz, 1H), 7.49 (dd, J =2.4, 8.84 Hz, 1H), 7.28 (d, J = 2.52 Hz, 1H), 7.25 (d, J = 8.92 Hz 1H),4.32 (m, 4H), 1.95 (s, 3H) 169

MS (ESI) m/z 554.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.77 (bs,1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.71 (d, J = 7.32 Hz, 1H), 7.36-7.28(m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 9.56 Hz, 2H), 6.57-6.50(q, J = 6.32, 11.64 Hz, 1H), 4.88 (d, J = 11.32 Hz, 1H), 4.64 (d, J =17.52 Hz, 1H), 4.30 (s, 4H), 2.02 (s, 3H) 181

MS (ESI) m/z 603.04 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H),8.50 (s, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.60-7.36 (m, 4H), 4.72 (d, J= 44 Hz, 2H), 4.39 (bs, 2H), 4.12 (bs, 2H) 182

MS (ESI) m/z 546.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H),8.30 (s, 1H), 7.87-7.83 (m, 2H), 7.55 (d, J = 7.50 Hz, 1H), 7.45-7.39(m, 2H), 7.30 (d, J = 2.48 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.10 (d, J= 45 Hz, 2H), 4.39 (bs, 4H) 185

MS (ESI) m/z 539.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H),8.60 (s, 1H), 8.50 (s, 1H), 7.87-7.71 (m, 2H), 7.53-7.51 (d, J = 8 Hz,1H), 7.43-7.37 (m, 2H), 7.35-7.20 (m, 2H), 4.53 (t, J = 4 Hz, 2H), 4.39(t, J = 4 Hz, 2H) 186

MS (ESI) m/z 530.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H),8.08 (s, 1H), 7.88 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.65 (s, 2H),7.41-7.33 (m, 3H), 7.22 (d, J = 8.72, 1H), 4.30-4.27 (t, J = 6 Hz, 2H),4.22-4.20 (t, J = 5.54 Hz, 2H) 187

MS (ESI) m/z 548.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H),8.47 (s, 1H), 8.29 (s, 1H), 7.88 (s, 1H), 7.77 (d, J = 7.50 Hz, 1H),7.59 (d, J = 7.90 Hz, 1H), 7.42-7.38 (m, 2H), 7.31 (d, J = 2.48 Hz, 1H),7.22 (d, J = 9.0 Hz, 1H), 4.52 (d, J = 4.72 Hz, 2H), 4.38 (d, J = 4.8Hz, 2H) 199

MS (ESI) m/z 584.69 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H),8.72 (d, 4.08 Hz, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.70 (s, 1H), 7.58(dd, J = 2.32, 8.52 Hz, 1H), 7.40 (d, J = 2.36 Hz, 1H), 7.35 (d, J =8.96 Hz, 2H), 4.42 (s, 2H), 4.26 (s, 2H), 1.81 (s, 3H) 201

MS (ESI) m/z 585.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.04 (b, 1H),8.30 (s, 1H), 8.25 (d, J = 5.56 Hz, 1H), 7.96 (d, J = 6.4 Hz, 2H),7.60-7.58 (m, 2H), 7.50 (dd, J = 8.8 Hz, 1H), 7.30 (d, J = 8.84 Hz, 1H),4.45 (t, J = 4.72 Hz, 2H), 4.36 (t, J = 4.6 Hz, 2H), 2.18 (s, 1H) 202

MS (ESI) m/z 599.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H),8.66 (d, 4.56 Hz, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 7.56 (m, 2H), 7.40(d, J = 2.44 Hz, 1H), 7.33 (d, J = 9.04 Hz, 1H), 7.26 (d, J = 4.6 Hz,1H), 4.38 (s, 2H), 4.25 (s, 2H), 3.84 (s, 2H), 1.78 ( s, 3H) 203

MS (ESI) m/z 589.91 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H),8.29 (s, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.48- 7.44 (m,2H), 7.29 (d, J = 8.8 Hz, 1H), 4.50 (m, 2H), 4.25 (s, 2H), 2.08 (s, 3H)205

MS (ESI) m/z 599.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =4.96 Hz, 1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.60 (dd, J = 8.88, 2.6 Hz,1H), 7.53 (d, J = 4.88 Hz, 1H), 7.43 (d, J = 2.56 Hz, 1H), 7.36 (d, J =8.96 Hz, 1H), 4.43 (s, 2H), 4.27 (s, 2H), 2.34 (s, 3H), 1.85 (s, 3H) 206

MS (ESI) m/z 619.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.64 Hz, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.60 (d, J = 8.84 Hz, 1H),7.52 (d, J = 4.4 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J = 8.92 Hz, 1H), 4.44(s, 2H), 4.28 (s, 2H), 1.81 (s, 3H) 210

MS (ESI) m/z 610.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H),8.82 (d, J = 4.64 Hz, 1H), 8.41 (d, J = 9.8 Hz, 2H), 7.6 (dd, J = 8.92,2.48 Hz, 1H), 7.45 (dd, J = 9.68, 4.72 Hz, 2H), 7.37 (d, J = 8.88 Hz,1H), 4.42 (t, J = 5.04 Hz , 2H), 4.27 (t, J = 5.2 Hz, 2H), 1.96 (s, 3H)214

MS (ESI) m/z 609.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.16 (bs,1H), 8.86 (d, J = 4.6 Hz, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.60 (d, J =8.96 Hz, 1H), 7.49 (d, J = 4.44 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J =9.04, 1H), 4.42 (bs, 2H), 4.28 (bs, 2H), 1.74 (s, 3H) 215

MS (ESI) m/z 585 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.10 (bs, 1H),9.33 (s, 1H), 8.38 (s, 2H), 7.98 (s, 1H), 7.64 (dd, J = 8.8, 2.4 Hz,1H), 7.45 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 4.45 (s, 2H),4.27 (s, 2H), 1.77 (s, 3H) 225

MS (ESI) m/z 585.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H),8.59 (d, J = 5.56 Hz, 1H), 8.35-8.32 (m, 2H), 8.05 (s, 1H), 7.93 (s,1H), 7.55 (dd, J = 9.0, 2.56 Hz, 1H), 7.33-7.30 (m, 1H), 4.38 (s, 2H),4.22 (s, 2H), 1.69 (s, 3H) 226

MS (ESI) m/z 585.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H),8.38 (s, 1H), 8.18 (s, 1H), 7.97 (t, J = 6.30 Hz, 2H), 7.55-7.52 (dd, J= 2.24, 2.32 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.30- 7.25 (m, 2H),4.45-4.29 (m, 4H), 1.98 (s, 3H) 227

MS (ESI) m/z 551.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.96 Hz, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.55 (t, J =7.16 Hz, 1H), 7.50 (d, J = 4.48 Hz, 1H), 7.34 (t, J = 5.6 Hz, 2H), 7.16(t, J = 7.40 Hz, 1H), 4.41 (s, 2H), 4.27 (s, 2H), 1.80 (s, 3H) 246

MS (ESI) m/z 603.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.84 Hz, 1H), 8.64 (s, 1H), 8.40 (d, J = 9.16 Hz, 1H), 7.60 (dd, J =8.92 Hz, 2.6 Hz, 1H), 7.49 (d, J = 4.84 Hz, 1H), 7.45 (d, J = 2.6 Hz,1H), 7.37 (d, J = 8.96 Hz, 1H), 4.44 (t, J = 4.8 Hz, 2H), 4.29 (t, J =4.64 Hz, 2H), 1.99 (s, 3H) 255

MS (ESI) m/z 581.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.16 (bs,1H), 8.83 (s, 1H), 7.77 (d, J = 4.4 Hz, 1H), 8.35 (s, 1H), 8.14 (s, 1H),7.87 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.42(d, J = 4.4 Hz, 1H), 6.50-6.44 (m, 1H), 5.98 (d, J = 16.0, 1H), 4.73 (d,J = 4.0, 2H), 2.38 (s, 3H) 259

MS (ESI) m/z 586.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H),8.80 (d, J = 4.92 Hz, 1H), 8.39 (d, J = 1.12 Hz, 1H), 8.35 (d, J = 2.80Hz, 1H), 8.25 (s, 1H), 7.98 (d, J = 2.80 Hz, 1H), 7.49 (d, J = 4.88 Hz,1H), 4.53 (t, J = 5.4 Hz, 2H), 4.41 (t, J = 5.2 Hz, 2H), 2.62 (s, 3H)261

MS (ESI) m/z 644.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83-8.79 (m,3H), 8.29 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.84 (d, J = 5.68 Hz,2H), 7.59 (dd, J = 2.56, J = 8.84 Hz, 1H), 7.51 (d, J = 4.8 Hz, 1H),7.44 (d, J = 2.60 Hz, 1H), 7.34 (d, J = 8.96 Hz, 1H) 4.38 (t, J = 5.76Hz, 2H), 4.22 (t, J = 4.60 Hz, 2H), 1.69 (s, 3H) 265

MS (ESI) m/z 591.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (bs,1H), 8.9 (s, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H),7.6 (dd, J = 8.8, 2.3 Hz, 1H), 7.5 (d, J = 9.0 Hz, 1H), 4.76 (t, J = 5.2Hz, 2H), 4.57 (t, J = 3.6 Hz, 2H), 2.56 (s, 3H) 266

MS (ESI) m/z 619.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.64 Hz, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.60 (d, J = 8.84 Hz, 1H),7.52 (d, J = 4.4 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J = 8.92 Hz, 1H), 4.44(s, 2H), 4.28 (s, 2H), 1.81 (s, 3H) 267

MS (ESI) m/z 609.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.04 (bs,1H), 8.88 (d, J = 4.8 Hz, 1H), 8.30 (d, J = 1.2 Hz, 1H), 8.03 (d, J =1.4 Hz, 1H), 7.61-7.56 (m, 2H), 7.42 (d, J = 2.8 Hz, 1H), 7.35 (d, J =8.8 Hz, 1H), 4.91 (s, 1H), 4.44 (t, J = 4.4 Hz, 2H), 4.26 (d, J = 4.4Hz, 2H), 1.73 (s, 3H) 272

MS (ESI) m/z 586.17 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 13.95 (bs,1H), 8.98 (d, J = 4.4 Hz, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.66 (d, J =4.0 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H) 7.49 (s, 1H), 7.36 (d, J = 9.2 Hz,1H), 4.45 (s, 2H), 4.28 (s, 2H), 1.74 (s, 3H) 275

MS (ESI) m/z 601.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 8.85 (d, J =4.80 Hz, 1H), 8.39 (s, 1H), 7.89 (s, 1H), 7.60 (dd, J = 8.88, 2.36 Hz,1H), 7.50 (d, J = 4.80 Hz, 1H), 7.42 (d, J = 2.44 Hz, 1H), 7.35 (d, J =8.96 Hz, 1H), 4.40 (t, J = 5.28 Hz, 2H). 4.23 (t, J = 4.40 Hz, 2H), 1.71(s, 3H) 285

MS (ESI) m/z 552.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J =4.8 Hz, 1H), 8.79 (d, J = 6.2 Hz, 1H), 8.64 (s, 1H), 8.40 (s, 1H), 8.34(s, 1H), 8.05 (s, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.55 (d, J = 4.7 Hz,1H), 4.62 (t, J = 4.2 Hz, 2H), 4.31 (t, J = 4.7 Hz, 2H), 1.75 (s, 3H)287

MS (ESI) m/z 576.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.28 (bs,1H), 8.84 (d, J = 4.8 Hz, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 8.05 (dd, J =8.6, 2.0 Hz, 1H), 8.01 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.52 (d, J =3.4 Hz, 1H), 7.5 (s, 1H), 4.51 (t, J = 4.8 Hz, 2H), 4.26 (t, J = 5.9 Hz,2H), 1.7 (s, 3H) 289

MS (ESI) m/z 594.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 ( d, J =4.5 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.00 (d, J = 8.52, 2H), 7.63 (d, J= 11.4 Hz, 1H), 7.49 (d, J = 4.28 Hz, 1H), 4.527 (s, 2H), 4.26 (s, 2H),1.683 (s, 3H) 291

MS (ESI) m/z 577.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H),8.91 (d, J = 4.72 Hz, 1H), 8.87 (s, 1H), 8.39 (s, 1H), 8.35 (s, 1H),8.17 (s, 1H), 8.05 (s, 1H), 7.54 (d, J = 4.72 Hz, 1H), 4.66 (s, 2H),4.27 (s, 2H), 1.79 (s, 3H) 292

MS (ESI) m/z 577.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H),8.87 (s, 1H), 8.38 (s, 1H), 8.27 (d, J = 8.7 Hz, 1H), 8.22 (s, 1H), 8.1(d, J = 4.9 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 4.68 (t, J = 4.2 Hz, 2H),4.55 (t, J = 4.4 Hz, 2H), 2.37 (s, 3H) 294

MS (ESI) m/z 603.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.84 Hz, 1H), 8.45 (s, 1H), 8.37 (d, J = 5.28 Hz, 1H), 7.60 (dd, J =8.56, 6.72, Hz, 1H), 7.49 (d, J = 4.56 Hz 1H), 7.43 (d, J = 2.04 Hz,1H), 7.37 (d, J = 8.88 Hz, 1H), 4.42 (t, J = 4.90, 2H), 4.27 (t, J =4.40 Hz, 2H), 1.86 (s, 3H) 295

MS (ESI) m/z 634.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6), 68.76 (d, J =2.68 Hz 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.74 (s, 1H), 7.58 (dd, J =9.24, 2.81 Hz, 1H), 7.42 (d, J = 2.80 Hz, 1H), 7.40 (d, J = 4.40 Hz,1H), 7.34 (d, J = 8.96 Hz, 1H), 4.45-4.37 (m, 2H), 4.30-4.22 (m, 2H),1.82 (s, 3H) 296

MS (ESI) m/z 599.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H),8.36 (s, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.60-7.57 (dd, J = 2.52, 8.8Hz, 1H), 7.41 (m, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.40 (t, J = 5 Hz,2H), 4.25 (t, J = 5.0 Hz, 2H), 2.69 (s, 3H), 1.82 (s, 3H) 299

MS (ESI) m/z 585.17 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 14.22 (bs,1H), 8.37 (s, 1H), 8.34 (d, J = 4.8 Hz, 1H), 8.18 (s, 1H), 7.98 (s, 1H),7.47-7.44 (m, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 9.2 Hz, 1H),4.34 (t, 4.8 Hz, 2H), 4.25 (t, J = 4.4, 2H), 1.97 (s, 3H) 300

MS (ESI) m/z 568.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H),8.33 (s,1H), 8.20 (s, 1H), 8.06 (s, 1H), 7.61 (d, J = 7.28 Hz, 1H), 7.51(d, J = 7.56 Hz, 1H), 7.47 (d, J = 2.32 Hz, 1H), 7.43 (d, J = 2.2 Hz,1H), 7.28 (d, J = 8.8 Hz, 1H), 6.97 (t, J = 7.56 Hz, 1H,), 4.43 (s, 2H),4.32 (s,2H), 2.10 (s, 3H) 301

MS (ESI) m/z 583.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.46 (bs,1H), 8.35 (s, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.55 (d, J = 7.32 Hz,1H), 7.49 (dd, J = 8.80, 2.68 Hz, 1H), 7.32-7.27 (m, 3H), 6.89 (t, J =7.64 Hz, 1H), 4.30 (t, J = 5.08 Hz, 2H), 4.16 (t, J = 5.12 Hz, 2H), 1.92(s, 3H) 314

MS (ESI) m/z 585.94 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H),9.18 (s, 1H), 8.33 (s, 1H), 8.24 (s, 1H), 7.97 ( s, 1H), 7.62 (dd, J =8.8, 2.7 Hz, 1H), 7.49 (d, J = 2.32 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H),4.44 (t, J = 4.96 Hz, 2H), 4.27 (t, J = 4.96 Hz, 2H), 1.71 (s, 3H) 315

MS (ESI) m/z 591.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.54 ( s,1H), 8.33 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.67 (d, J = 2.64 Hz,1H), 7.59 (dd, J = 8.92, 2.68 Hz, 1H), 7.38 (d, J = 9 Hz, 1H), 4.60 (t,J = 5.24 Hz, 2H), 4.37 (t, J = 5.36 Hz, 2H), 2.14 (s, 3H) 319

MS (ESI) m/z 585.2 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO)/ppm = 13.31 (bs,1H), 9.59 (s, 1H), 8.37 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 7.95-7.94 (m,1H), 7.91 (s, 1H), 7.54 (dd, J = 8.9, 2.6 Hz, 1H), 7.38 (d, J = 2.6 Hz,1H), 7.30 (d, J = 8.9 Hz, 1H), 4.36 (t, J = 4.7 Hz, 2H), 4.21 (t, J =4.7 Hz, 2H), 1.70 (s, 3H) 320

MS (ESI) m/z 582.1 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) / ppm = 8.49 (d,J = 5.1 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.15-8.02 (m, 2H), 7.60 (dd,J = 9.1, 2.6 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.30 (d, J = 9.1 Hz,1H), 7.34-7.20 (m, 1H), 4.46-4.33 (m, 2H), 4.28- 4.20 (m, 2H), 3.16 (s,3H), 1.66 (s, 3H) 321

MS (ESI) m/z 700.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H),8.87-8.81 (m, 1H), 8.24-8.17 (m, 1H), 7.98 (s, 1H), 7.61 (dd, J = 8.9,2.7 Hz, 1H), 7.49 (dd, J = 4.9, 2.0 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H),7.37 (d, J = 9.0 Hz, 1H), 4.77-4.71 (m, 1H), 4.66-4.59 (m, 1H), 4.42 (t,J = 5.0 Hz, 2H), 4.32-4.11 (m, 6H), 3.70-3.53 (m, 2H), 3.23- 3.11 (m,2H), 1.81 (s, 3H) 322

[0503] MS (ESI) m/z 567.2 [M + 1]+; 1H NMR (400 MHz, d6-DMSO) δ/ppm =11.04 (d, J = 3.2 Hz, 1H), 8.38-8.37 (m, 1H), 8.10-8.08 (m, 1H), 8.02(d, J = 8.1 Hz, 1H), 7.45 (dd, J = 8.9 Hz, 2.8 Hz, 1H), 7.25-7.15 (m,4H), 7.02 (dd, J = 7.2, 1.2 Hz, 1H), 4.40-4.35 (m, 2H), 4.22- 4.18 (m,2H), 1.61 (s, 3H) 323

MS (ESI) m/z 568.0 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 13.49 (b,1H), 8.59 (d, J = 5.6 Hz, 1H), 8.40-8.39 (m, 1H), 8.07- 8.05 (m, 1H),7.87-7.77 (m, 1H), 7.62 (dd, J = 8.9, 2.6 Hz, 1H), 7.60-7.49 (m, 1H),7.42 (d, J = 2.6 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 4.45 (t, J = 4.6 Hz,2H), 4.25 (t, J = 4.6 Hz, 2H), 1.76 (s, 3H) 324

MS (ESI) m/z 569.0 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.80 (s,1H), 8.65 (d, J = 4.9 Hz, 1H), 8.53 (d, J = 2.7 Hz, 1H), 8.33 (bd, J =1.7 Hz, 1H), 8.15-8.14 (m, 1H), 7.69 (d, J = 4.9 Hz, 1H), 7.43 (dd, J =8.9, 2.7 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 4.55-4.52 (m, 4H), 2.45 (s,3H) 325

MS (ESI) m/z 569.0 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.98-8.90(m, 1H), 8.54-8.45 (m, 1H), 8.36-8.31 (m, 1H), 8.23-8.18 (m, 1H),7.64-7.51 (m, 3H), 7.34-7.27 (m, 1H), 4.43-4.34 (m, 2H), 4.34- 4.23 (m,2H), 1.77 (s, 3H) 326

[0506] MS (ESI) m/z 535.1 [M + 1]+ 327

MS (ESI) m/z 616.4 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.33 (bd,J = 1.7 Hz, 1H), 8.24 (dd, J = 7.8, 0.9 Hz, 1H), 7.95 (s, 1H), 7.76 (dd,J = 7.8, 7.8 Hz, 1H), 7.50 (dd, J = 8.9, 2.6 Hz, 1H), 7.45 (bd, J = 7.8Hz, 1H), 7.23-7.20 (m, 2H), 7.14 (s, 1H), 4.36-4.21 (m, 4H), 1.84 (s,3H) 328

MS (ESI) m/z 549.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.39 (bd,J = 1.7 Hz, 1H), 8.24-8.22 (m, 1H), 7.01-6.87 (m, 3H), 4.52 (t, J = 4.8Hz, 2H), 4.35 (t, J = 4.8 Hz, 2H), 3.22-3.16 (m, 2H), 2.80 (s, 3H),2.50-2.43 (m, 2H), 2.13-2.09 (m, 2H), 1.74-1.57 (m, 3H), 1.27-1.11 (m,2H) 329

MS (ESI) m/z 615.0 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.36 (bd,J = 1.6 Hz, 1H), 8.12 (s, 1H), 8.01-8.00 (m, 1H), 7.57 (dd, J = 8.9, 2.7Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H), 7.33 (d, J = 8.9 Hz, 1H), 6.90 (d, J= 0.3 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.26 (t, J = 5.0 Hz, 1H), 4.03(s, 3H), 1.87 (s, 3H) 330

MS (ESI) m/z 613.1 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.37 (bs,1H), 8.24 (s, 1H), 7.95 (bs, 1H), 7.60 (dd, J = 8.8, 2.6, 1H), 7.47 (s,1H), 7.43 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 4.41 (bt, 2H),4.25 (bt, 2H), 3.01 (q, J = 7.6 Hz, 2H), 1.78 (s, 3H), 1.34 (t, J = 7.6Hz, 3H) 331

MS (ESI) m/z 601.6 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 10.48 (s,1H), 8.37-8.36 (m, 1H), 7.95 (bs, 1H), 7.78 (bs, 1H), 7.56 (dd, J = 8.7,2.6, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 6.36 (bs,1H), 4.41 (bt, 2H), 4.32 (bt, 2H), 2.15 (s, 3H) 332

MS (ESI) m/z 615.1 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 13.35 (b,1H), 8.32 (d, J = 1.2 Hz, 1H), 8.06-8.04 (m, 1H), 7.68 (s, 1H), 7.51(dd, J = 8.8, 2.7 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.26 (d, J = 8.8Hz, 1H), 6.35 (s, 1H), 4.35 (bt, 1H), 4.28 (bt, 1H), 3.65 (s, 3H), 2.06(s, 3H) 333

MS (ESI) m/z 616.2 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 12.89 (b,1H), 8.35 (d, J = 1.5 Hz, 1H), 8.07 (bs, 1H), 7.77 (bs, 1H), 7.50 (dd, J= 8.9, 2.7 Hz, 1H), 7.30-7.26 (m, 2H), 7.19 (d, J = 6.0 Hz, 1H), 4.35(bt, 2H), 4.25 (bt, 2H), 2.33 (s, 3H), 1.83 (s, 3H) 341

MS (ESI) m/z 690.1 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.75 (d,J = 5.3 Hz, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.60 (dd, J = 8.9, 2.8 Hz,1H), 7.59 (s, 1H), 7.52 (bd, J = 5.3 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J =2.8 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 4.42 (t, J = 5.2 Hz, 2H), 4.28(t, J = 5.2 Hz, 2H), 2.73 (s, 3H), 2.64 (s, 3H), 1.87 (s, 3H) 342

MS (ESI) m/z 694.2 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.82 (d,J = 2.8 Hz, 1H), 8.60-8.59 (m, 1H), 8.28 (s, 1H), 8.11-8.06 (m, 1H),8.07 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J =2.7 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 4.43 (t, J = 4.9 Hz, 2H), 4.29(t, J = 4.9 Hz, 2H), 2.73 (s, 3H), 1.89 (s, 3H) 343

MS (ESI) m/z 694.5 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.85 (dd,J = 7.5, 5.8 Hz, 1H), 8.79 (d, J = 9.9 Hz, 1H), 8.35 (s, 1H), 8.12 (s1H), 7.64 (dd, J = 9.8, 5.8 Hz 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.47(s, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 4.49-4.19(m, 4H), 2.73 (s, 3H), 1.87 (s, 3H) 344

MS (ESI) m/z 694.2 [M + 1]+; 1H-NMR (400 MHz, d6- DMSO) δ/ppm = 8.87 (s,1H), 8.71 (d, J = 4.7 Hz, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.74-7.70 (m,1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 2.7 Hz,1H), 7.36 (d, J = 8.9 Hz, 1H), 4.48-4.20 (m, 4H), 2.72 (s, 3H), 1.87 (s,3H) 347

MS (ESI) m/z 682.5 [M + 1]+; 1H-NMR (400 MHz, d6- DMSO) δ/ppm = 9.32 (s,1H), 8.71 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.60 (dd, J = 8.9, 2.7Hz, 1H), 7.44 (s, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 8.9 Hz,1H), 4.42 (t, J = 4.7 Hz, 2H), 4.28 (t, J = 4.7 Hz, 2H), 2.72 (s, 3H),1.88 (s, 3H) 348

MS (ESI) m/z 682.4 [M + 1]+; 1H-NMR (400 MHz, d6- DMSO) δ/ppm = 8.74 (d,J = 1.7 Hz, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.67 (d, J = 1.7 Hz, 1H),7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.47 (s, 1H), 7.43 (d, J = 2.7 Hz, 1H),7.36 (d, J = 8.6 Hz, 1H), 4.42 (t, J = 4.9 Hz, 2H), 4.28 (t, J = 4.9 Hz,2H), 2.74 (s, 3H), 1.86 (s, 3H) 349

MS (ESI) m/z 704.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.28 (s,1H), 8.08 (s, 1H), 7.83-7.77 (m, 1H), 7.60 (dd, J = 9.0, 2.8 Hz, 1H),7.46 (s, 1H), 7.44 (d, J = 2.8 Hz, 1H), 7.43-7.38 (m, 1H), 7.37 (d, J =9.0 Hz, 1H), 4.47-4.38 (m, 2H), 4.33-4.19 (m, 2H), 2.73 (s, 3H), 2.59(s, 3H), 2.22 (s, 3H), 1.84 (s, 3H) 350

MS (ESI) m/z 704.5 [M + 1]⁺; 1H-NMR (400 MHz, d6-DMSO) □/ppm = 8.47-8.37(m, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H),7.46 (s, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.43-7.39 (m, 1H), 7.37 (d, J =8.9 Hz, 1H), 4.47-4.43 (m, 2H), 4.34-4.18 (m, 2H), 2.73 (s, 3H), 2.57(s, 3H), 2.06 (s, 3H), 1.84 (s, 3H) 352

MS (ESI) m/z 599.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J =4.7 Hz, 1H), 8.38 (dd, J = 1.8, 0.6 Hz, 1H), 8.22 (dt, J = 1.8, 0.8 Hz,1H), 7.53 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J = 2.7 Hz,1H), 7.29 (d, J = 9.0 Hz, 1H), 7.21 (d, J = 4.7 Hz, 1H), 5.43 (s, 1H),4.37 (t, J = 4.9 Hz, 2H), 4.24 (t, J = 4.9 Hz, 2H), 1.75 (s, 6H), 1.65(s, 3H) 354

MS (ESI) m/z 615.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.87-8.84 (m,2H), 7.61-7.57 (m, 2H), 7.53-7.51 (m, 2H), 7.38 (d, J = 9.0 Hz, 1H),7.35 (s, 1H), 4.23 (t, J = 5.5 Hz, 2H), 3.74 (t, J = 5.4 Hz, 2H), 2.75(s, 3H), 1.07 (s, 6H) 356

MS (ESI) m/z 602.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H),8.82 (d, J = 4.9 Hz, 1H), 8.45 (s, 1H), 8.37-8.36 (m, 1H), 8.05-8.04 (m,1H), 7.95 (s, 1H), 7.52 (d, J = 4.9 Hz, 1H), 4.63 (t, J = 5.0 Hz, 2H),4.31 (t, J = 5.0 Hz, 2H), 1.90 (s, 3H) 363

MS (ESI) m/z 613.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H),7.92 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.41 (d, J =2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 5.0 Hz, 2H), 4.25(t, J = 5.0 Hz, 2H), 2.71 (s, 3H), 2.70 (s, 3H), 1.85 (s, 3H) 364

MS (ESI) m/z 613.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H),8.16 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.41 (d, J =2.7 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 4.44 (t, J = 5.0 Hz, 2H), 4.26(t, J = 5.0 Hz, 2H), 2.68 (s, 3H), 2.69-2.63 (m, 3H), 1.93 (s, 3H) 373

MS (ESI) m/z 694.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H),8.25 (d, J = 5.1 Hz, 1H), 7.98 (d, J = 5.3 Hz, 1H), 7.60 (dd, J = 8.9,2.6 Hz, 1H), 7.44 (s, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.0Hz, 1H), 5.95 (s, 1H), 4.41 (t, J = 5.4 Hz, 2H), 4.26 (t, J = 5.1 Hz,2H), 4.13 (d, J = 17.4 Hz, 1H), 3.84 (d, J = 17.8 Hz, 1H), 3.02-2.88 (m,5H), 2.73-2.66 (m, 5H), 1.87 (s, 3H) 374

MS (ESI) m/z 626.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H),8.15 (s, 1H), 7.83 (dt, J = 7.7, 1.5 Hz, 1H), 7.80 (t, J = 1.8 Hz, 1H),7.50 (dt, J = 7.7, 1.6 Hz, 1H), 7.45- 7.38 (m, 2H), 7.28 (d, J = 2.7 Hz,1H), 7.21 (d, J = 8.9 Hz, 1H), 3.85 (t, J = 12.3 Hz, 2H), 3.54 (d, J =11.7 Hz, 2H), 3.19 (d, J = 12.8 Hz, 2H), 3.12-2.99 (m, 2H), 2.89 (s,3H), 2.21 (s, 3H) 375

MS (ESI) m/z 619.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H),7.92-7.85 (m, 2H), 7.84 (t, J = 1.8 Hz, 1H), 7.54 (dt, J = 7.8, 1.6 Hz,1H), 7.45 (d, J = 7.6 Hz, 1H), 7.43-7.37 (m, 3H), 7.29 (d, J = 2.6 Hz,1H), 7.21 (d, J = 8.9 Hz, 1H), 4.40- 4.33 (m, 4H), 2.52 (s, 3H), 2.24(s, 3H) 376

MS (ESI) m/z 717.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H),7.49 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.0 Hz,1H), 6.38 (tt, J = 53.3, 3.0 Hz, 1H), 4.42 (t, J = 5.1 Hz, 2H),4.31-4.25 (m, 6H), 3.87 (td, J = 16.3, 3.0 Hz, 2H), 3.41 (s, 2H), 3.24(s, 1H), 1.81 (s, 3H) 377

MS (ESI) m/z 676.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H),7.85-7.78 (m, 2H), 7.51 (dt, J = 7.7, 1.5 Hz, 1H), 7.44-7.37 (m, 2H),7.28 (d, J = 2.7 Hz, 1H), 7.21 (d, J = 8.9 Hz, 1H), 6.38 (t, J = 54.0Hz, 1H), 2.20 (s, 3H). Note: some aliphatic signals were very broad andcould not be integrated 378

MS (ESI) m/z 654.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H),7.85-7.79 (m, 2H), 7.51 (dt, J = 7.7, 1.6 Hz, 1H), 7.44- 7.37 (m, 2H),7.27 (d, J = 2.6 Hz, 1H), 7.21 (d, J = 8.9 Hz, 1H), 4.34 (s, 4H),3.06-2.76 (m, 2H), 2.20 (s, 3H), 2.06 (s, 3H) Note: some aliphaticsignals were very broad and could not be integrated 379

MS (ESI) m/z 689.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H),8.11 (dd, J = 5.6, 1.9 Hz, 1H), 7.87-7.79 (m, 3H), 7.51 (dt, J = 7.7,1.6 Hz, 1H), 7.45-7.38 (m, 2H), 7.28 (d, J = 2.7 Hz, 1H), 7.21 (d, J =8.9 Hz, 2H), 6.85 (t, J = 6.3 Hz, 1H), 4.35 (s, 4H), 2.20 (s, 3H). Note:some aliphatic signals were very broad and could not be integrated 380

MS (ESI) m/z 689.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J =2.9 Hz, 1H), 8.22 (d, J = 5.3 Hz, 1H), 8.15 (s, 1H), 8.08 (dd, J = 8.8,2.8 Hz, 1H), 7.85 (dt, J = 7.7, 1.5 Hz, 1H), 7.83-7.78 (m, 2H), 7.51(dt, J = 7.7, 1.6 Hz, 1H), 7.45-7.38 (m, 2H), 7.28 (d, J = 2.7 Hz, 1H),7.21 (d, J = 8.9 Hz, 1H), 4.35 (s, 4H), 2.20 (s, 3H). Note: somealiphatic signals were very broad and could not be integrated 381

MS (ESI) m/z 640.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H),7.84 (dt, J = 7.7, 1.5 Hz, 1H), 7.80 (t, J = 1.8 Hz, 1H), 7.51 (dt, J =7.7, 1.5 Hz, 1H), 7.45-7.38 (m, 2H), 7.27 (d, J = 2.6 Hz, 1H), 7.21 (d,J = 8.9 Hz, 1H), 4.35 (s, 4H), 2.92 (s, 3H), 2.19 (s, 3H). Note: somealiphatic signals were very broad and could not be integrated 382

MS (ESI) m/z 688.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H),7.87-7.80 (m, 2H), 7.52 (dt, J = 7.7, 1.5 Hz, 1H), 7.45-7.37 (m, 2H),7.30- 7.19 (m, 4H), 7.05-6.99 (m, 2H), 6.83 (t, J = 7.3 Hz, 1H), 4.35(s, 4H), 2.20 (s, 3H). Note: some aliphatic signals were very broad andcould not be integrated 383

MS (ESI) m/z 711.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H),7.92 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J =2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.1 Hz, 2H), 4.24(t, J = 5.0 Hz, 2H), 2.94 (s, 3H), 2.72 (s, 3H), 1.82 (s, 3H). Note:some aliphatic signals were very broad and could not be integrated 386

MS (ESI) m/z 605.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =5.1 Hz, 2H), 8.29 (s, 1H), 7.86 (dt, J = 7.6, 1.6 Hz, 1H), 7.82 (t, J =1.8 Hz, 1H), 7.55-7.50 (m, 3H), 7.47-7.39 (m, 2H), 7.28 (d, J = 2.7 Hz,1H), 7.22 (d, J = 8.9 Hz, 1H), 4.43-4.31 (m, 4H), 2.24 (s, 3H) 387

MS (ESI) m/z 689.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J =7.4 Hz, 2H), 7.88 (s, 1H), 7.45-7.34 (m, 5H), 7.26 (d, J = 2.7 Hz, 1H),7.19 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 7.1 Hz, 2H), 4.31 (s, 4H),3.85-3.49 (m, 8H), 2.20 (s, 3H) 388

MS (ESI) m/z 605.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (dd, J =4.9, 1.6 Hz, 1H), 8.62 (s, 1H), 8.28 (s, 1H), 7.91 (dt, J = 7.9, 1.9 Hz,1H), 7.86 (dt, J = 7.6, 1.5 Hz, 1H), 7.82 (t, J = 1.8 Hz, 1H), 7.62 (dd,J = 7.8, 4.8 Hz, 1H), 7.53 (dt, J = 7.7, 1.5 Hz, 1H), 7.48- 7.38 (m,2H), 7.28 (d, J = 2.6 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 4.42-4.32 (m, J= 2.5 Hz, 4H), 2.24 (s, 3H) 389

MS (ESI) m/z 703.9 [M + 1]+;; 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H),8.27 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz,1H), 7.46 (s, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H),4.43 (t, J = 5.0 Hz, 2H), 4.28 (t, J = 4.9 Hz, 2H), 2.73 (s, 3H), 2.64(s, 3H), 2.42 (s, 3H), 1.88 (s, 3H) 398

MS (ESI) m/z 656.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.16 (t, J =5.4 Hz, 1H), 8.34 (d, J = 1.7 Hz, 1H), 8.14 (s, 1H), 8.05 (dd, J = 1.8,0.8 Hz, 1H), 7.58 (dd, J = 8.9, 2.7 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H),7.34 (d, J = 9.0 Hz, 1H), 7.33 (s, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.26(t, J = 5.0 Hz, 2H), 4.21 (d, J = 5.4 Hz, 2H), 2.69 (s, 3H), 1.84 (s,3H) 401

MS (ESI) m/z 568.2 [M + H]+; 1H NMR (400 MHz, CD3OD) δ 8.16-8.13 (m,1H), 8.05-8.02 (m, 1H), 7.97 (s, 1H), 7.90 (dd, J = 7.9, 1.3 Hz, 1H),7.41 (dd, J = 8.8, 2.7 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.23 (d, J =2.7 Hz, 1H), 7.20 (dd, J = 7.4, 1.3 Hz, 1H), 7.19 (d, J = 8.9 Hz, 1H),4.40-4.30 (m, 4H), 1.98 (s, 3H) 402

MS (ESI) m/z 584.3 [M + H]+; 1H NMR (400 MHz, Methanol-d4) δ 8.52 (dd, J= 8.3, 1.1 Hz, 1H), 8.15 (dd, J = 1.8, 0.6 Hz, 1H), 8.01 (dd, J = 1.7,0.8 Hz, 1H), 7.77 (s, 1H), 7.51 (dd, J = 8.2, 7.2 Hz, 1H), 7.45 (dd, J =8.9, 2.7 Hz, 1H), 7.30-7.25 (m, 1H), 7.22 (s, 1H), 7.21-7.16 (m, 1H),4.40 (t, J = 4.8 Hz, 2H), 4.31 (t, J = 4.8 Hz, 2H), 1.82 (s, 3H) 410

MS (ESI) m/z 543.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J =1.7 Hz, 1H), 8.17 (bs, 1H), 7.77 (bd, J = 1.6 Hz, 1H), 7.48 (bd, J = 1.4Hz, 1H), 7.47 (dd, J = 8.9, 2.7 Hz, 1H), 7.36 (d, J = 2.7 Hz, 1H), 7.25(d, J = 8.9 Hz, 1H), 4.39 (bs, 4H), 2.51 (s, 3H), 2.24 (s, 3H) 411

MS (ESI) m/z 557.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J =1.7 Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.49 (dd, J = 8.9, 2.7 Hz, 1H),7.46-7.40 (br, 2H), 7.37 (d, J = 2.7 Hz, 1H), 7.26 (d, J = 8.9 Hz, 1H),4.49-4.35 (m, 4H), 3.86 (s, 2H), 2.53 (s, 3H), 2.31 (s, 3H) 414

MS (ESI) m/z 583.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J =1.8 Hz, 1H), 8.10 (br, 1H), 7.97 (s, 1H), 7.62 (dd, J = 8.9, 2.7 Hz,1H), 7.53 (d, J = 2.7 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.15 (s, 1H),4.37 (t, J = 4.9 Hz, 2H), 4.25 (t, J = 4.9 Hz, 2H), 2.59 (s, 3H), 1.85(s, 3H) 415

MS (ESI) m/z 599.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (bs, 1H),8.24 (s, 1H), 7.95 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.50 (bs, 1H),7.42 (bs, 1H), 7.36 (d, J = 7.8 Hz), 4.40 (bs, 2H), 4.25 (bs, 2H), 2.72(s, 3H), 1.76 (s, 3H) 416

MS (ESI) m/z 599.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.6 Hz, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 7.60 (dd, J = 9.4, 2.6 Hz, 1H),7.49 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz,1H), 4.44 (t, J = 4.8 Hz, 2H), 4.26 (t, J = 4.8 Hz, 2H), 2.67 (s, 3H),1.84 (s, 3H) 417

MS (ESI) m/z 725.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H),7.60 (dd, J = 8.8, 2.6 Hz, 1H), 7.44 (s, 1H), 7.42 (d, J = 2.7 Hz, 1H),7.36 (d, J = 9.0 Hz, 1H), 4.42 (t, J = 5.0 Hz, 2H), 4.27 (t, J = 5.0 Hz,2H), 3.94 (s, 2H), 3.43-3.29 (m, 4H), 2.99-2.82 (m, 4H), 2.78 (d, J =4.3 Hz, 3H), 2.70 (s, 3H), 2.31 (s, 3H), 1.91 (s, 3H) 421

MS (ESI) m/z 690.7 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (dt, J =4.8, 1.4 Hz, 1H), 8.08-7.99 (m, 2H), 7.65-7.53 (m, 3H), 7.45 (s, 1H),7.42 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.42 (t, J = 4.9 Hz,2H), 4.28 (br, 2H), 2.72 (s, 3H), 2.48 (s, 3H), 1.94 (s, 3H) 422

MS (ESI) m/z 668.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H),7.92 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (dd, J = 4.3, 1.8 Hz,2H), 7.36 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.24 (t, J =5.0 Hz, 2H), 3.37-3.28 (m, 4H), 2.70 (s, 3H), 2.10-1.99 (m, 4H), 1.82(s, 3H) 423

MS (ESI) m/z 682.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H),7.89 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.44 (s, 1H), 7.42 (d, J =2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 5.04 (br, 6H), 4.39 (t, J = 5.0Hz, 2H), 4.23 (t, J = 5.0 Hz, 2H), 3.21 (br, 4H), 2.71 (s, 3H), 1.80 (s,3H) 424

MS (ESI) m/z 668.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H),7.95 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J =2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 5.0 Hz, 2H), 4.26(t, J = 5.0 Hz, 2H), 4.11-3.92 (m, 4H), 3.39 (br, 2H), 3.35-3.21 (m,1H), 2.71 (s, 3H), 1.85 (s, 3H) 425

MS (ESI) m/z 682.5 [M + 1]+; 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H),8.12 (s, 1H), 7.47 (dd, J = 8.9, 2.6 Hz, 1H), 7.26 (s, 1H), 7.18 (s,1H), 7.03 (d, J = 8.9 Hz, 1H), 4.56 (t, J = 9.0 Hz, 2H), 4.40 (t, J =4.8 Hz, 2H), 4.29 (t, J = 4.9 Hz, 2H), 3.84 (t, J = 9.6 Hz, 2H), 3.49(d, J = 6.6 Hz, 2H), 3.45-3.29 (m, 1H), 2.89 (s, 3H), 2.80 (s, 3H), 1.89(s, 3H) 428

MS (ESI) m/z 747.7 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H),7.91 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J =2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.38 (br, 1H), 4.40 (t, J = 5.0Hz, 2H), 4.24 (t, J = 5.0 Hz, 3H), 4.06-2.83 (br, 10H), 2.71 (s, 3H),1.83 (s, 3H) 429

MS (ESI) m/z 681.7 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H),7.96 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (dd, J = 7.3, 2.1 Hz,2H), 7.36 (d, J = 9.0 Hz, 1H), 5.92 (s, 1H), 4.41 (t, J = 5.0 Hz, 2H),4.29-4.15 (m, 4H), 3.86 (m, 4H), 2.71 (s, 3H), 1.85 (s, 3H) 430

MS (ESI) m/z 729.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H),7.93 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J =2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.95 (t, J = 4.4 Hz, 1H), 4.82(d, J = 4.6 Hz, 1H), 4.41 (t, J = 5.0 Hz, 2H), 4.25 (t, J = 5.0 Hz, 2H),3.65-3.03 (br, 10H), 2.72 (s, 3H), 1.85 (s, 3H) 431

MS (ESI) m/z 683.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H),8.50 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H),7.40 (s, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.35 (t, J = 5.1 Hz, 2H), 4.26(t, J = 5.1 Hz, 2H), 3.98 (dd, J = 11.3, 4.0 Hz, 2H), 3.43 (t, J = 11.3Hz, 2H), 3.22 (m, 1H), 2.72 (s, 3H), 2.08 (s, 3H), 2.03-1.88 (m, 2H),1.59 (d, J = 12.6 Hz, 2H) 433

MS (ESI) m/z 712.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =2.4 Hz, 1H), 8.42 (s, 1H), 8.33 (td, J = 9.1, 2.4 Hz, 1H), 8.17 (s, 1H),7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.44 (s, 1H),7.35 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.27 (t, J = 5.1 Hz,2H), 2.70 (s, 3H), 1.84 (s, 3H) 434

MS (ESI) m/z 708.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H),8.15 (s, 1H), 7.89 (t, J = 8.9 Hz, 1H), 7.62-7.53 (m, 2H), 7.45 (s, 1H),7.44 (d, J = 2.6, 0.9 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 4.40 (t, J =5.0 Hz, 2H), 4.28 (d, J = 5.0 Hz, 2H), 2.71 (s, 3H), 2.52 (s, 3H), 1.82(s, 3H) 437

MS (ESI) m/z 705.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H),8.27 (s, 1H), 8.10 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.46 (s,1H), 7.43 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.43 (t, J =5.1 Hz, 2H), 4.28 (tt, J = 9.5, 5.0 Hz, 2H), 2.74 (s, 3H), 2.71 (s, 3H),2.23 (s, 3H), 1.85 (s, 3H) 442

MS (ESI) m/z 691.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J =2.1 Hz, 1H), 8.26 (s, 1H), 8.08 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.60(dd, J = 8.9, 2.6 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.37(d, J = 9.0 Hz, 1H), 4.43 (t, J = 5.0 Hz, 2H), 4.29 (t, J = 5.0 Hz, 2H),2.77 (s, 3H), 2.73 (s, 3H), 1.89 (s, 3H) 443

MS (ESI) m/z 604.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J =4.8 Hz, 1H), 8.36-8.32 (m, 1H), 8.15-8.11 (m, 1H), 7.52 (dd, J = 8.9,2.7 Hz, 1H), 7.38 (d, J = 2.7 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 7.23(d, J = 4.8 Hz, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.25 (d, J = 5.0 Hz, 2H),1.88 (s, 3H), 1.33 (s, 9H) 444

MS (ESI) m/z 619.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J =1.9 Hz, 1H), 8.22 (s, 1H), 7.97 (dd, J = 1.9, 0.8 Hz, 1H), 7.56 (dd, J =8.9, 2.7 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.31 (d, J =9.0 Hz, 1H), 4.37 (t, J = 5.0 Hz, 2H), 4.23 (t, J = 5.0 Hz, 2H), 1.79(s, 3H) 445

MS (ESI) m/z 628.7 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J =1.8 Hz, 1H), 8.25 (s, 1H), 8.01 (d, J = 3.1 Hz, 1H), 7.94 (dd, J = 1.8,0.9 Hz, 1H), 7.89 (s, 2H), 7.57 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (d, J =2.6 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 4.37 (t, J = 5.0 Hz, 2H), 4.20(t, J = 5.0 Hz, 2H), 1.65 (s, 3H) 446

MS (ESI) m/z 610.7 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J =1.1 Hz, 1H), 8.35 (d, J = 1.7 Hz, 1H), 8.01-7.97 (m, 2H), 7.58 (ddd, J =9.1, 2.7, 1.0 Hz, 1H), 7.44 (dd, J = 2.6, 1.0 Hz, 1H), 7.33 (d, J = 9.0Hz, 1H), 4.38 (t, J = 5.0 Hz, 2H), 4.23 (t, J = 5.0 Hz, 2H), 1.71 (s,3H) 447

MS (ESI) m/z 599.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.37-8.31 (m,1H), 7.97 (d, J = 1.3 Hz, 1H), 7.95 (dt, J = 1.8, 0.8 Hz, 1H), 7.55 (dd,J = 8.9, 2.7 Hz, 1H), 7.35-7.28 (m, 2H), 7.17 (d, J = 0.9 Hz, 1H), 4.36(t, J = 5.0 Hz, 2H), 4.20 (t, J = 5.0 Hz, 2H), 2.65 (d, J = 0.7 Hz, 3H),1.86 (s, 3H) 452

MS (ESI) m/z 614.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H),8.50-8.37 (m, 4H), 8.30 (s, 1H), 8.01 (s, 1H), 7.62 (dd, J = 8.9, 2.7Hz, 1H), 7.57 (s, 1H), 7.40-7.35 (m, 2H), 4.44 (q, J = 6.1 Hz, 4H), 4.27(t, J = 5.2 Hz, 2H), 1.77 (s, 3H) 453

MS (ESI) m/z 552.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (dd, J =6.2, 0.7 Hz, H), 8.89-8.84 (m, 2H), 8.37-8.33 (m, 1H), 8.20 (dt, J =1.8, 0.8 Hz, 1H), 8.07-8.03 (m, 1H), 7.66 (dd, J = 6.2, 0.8 Hz, 1H),4.63 (t, J = 5.0 Hz, 2H), 4.53 (t, J = 5.0 Hz, 2H), 3.88 (s, 1H), 2.33(s, 3H) 454

MS (ESI) m/z 587.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H),8.96 (s, 1H), 8.93 (d, J = 5.0 Hz, 1H), 8.39-8.37 (m, 1H), 8.26 (d, J =5.0 Hz, 1H), 8.24 (dd, J = 1.7, 0.8 Hz, 1H), 4.77 (t, J = 5.1 Hz, 2H),4.62 (t, J = 5.1 Hz, 2H), 2.53 (s, 3H) 455

MS (ESI) m/z 578.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H),8.92 (s, 2H), 8.35 (s, 1H), 8.20 (d, J = 4.9 Hz, 2H), 4.83 (s, 2H), 4.60(s, 2H), 2.56 (2, 3H) 465

LCMS: 704.5 [M + H]+; 1H NMR (400 MHz, DMSO- d6) δ 8.25 (s, 1H), 8.05(s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.50-7.33 (m, 4H), 4.42 (t, J =5.0 Hz, 2H), 4.28 (t, J = 5.0 Hz, 2H), 2.73 (s, 3H), 2.62 (s, 6H), 1.87(s, 3H) 466

LCMS: 704.5 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74-8.65 (m, 1H),8.32 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.60 (dd, J = 8.9,2.7 Hz, 1H), 7.49-7.41 (m, 3H), 7.37 (d, J = 9.0 Hz, 1H), 4.52-4.10 (m,2H), 2.73 (s, 3H), 2.45-2.35 (m, 2H), 1.85 (s, 3H), 1.15 (t, J = 7.5 Hz,3H) 468

LCMS: 704.5 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 5.2 Hz,1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.57(s, 1H), 7.52-7.47 (m, 1H), 7.45 (s, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.37(d, J = 9.0 Hz, 1H), 4.42 (t, J = 5.1 Hz, 2H), 4.29 (d, J = 5.2 Hz, 2H),2.91 (q, J = 7.5 Hz, 2H), 2.73 (s, 3H), 1.87 (s, 3H), 1.29 (t, J = 7.6Hz, 3H) 469

LCMS: 704.5 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.25 (s,1H), 8.11 (s, 1H), 7.63-7.58 (m, 2H), 7.47 (s, 1H), 7.44 (d, J = 2.6 Hz,1H), 7.37 (d, J = 9.0 Hz, 1H), 4.43 (h, J = 5.9 Hz, 2H), 4.27 (dd, J =11.3, 5.7 Hz, 1H), 2.74 (s, 3H), 2.64 (s, 3H), 2.08 (s, 3H), 1.84 (s,3H) 470

LCMS: 708.5 [M + H]+; 1H NMR (400 MHz, DMSO- d6) δ 8.70-8.65 (m, 1H),8.27 (d, J = 0.9 Hz, 1H), 8.10 (s, 1H), 7.91 (dd, J = 9.0, 2.9 Hz, 1H),7.60 (ddd, J = 8.9, 2.6, 1.0 Hz, 1H), 7.47-7.41 (m, 2H), 7.37 (d, J =8.9 Hz, 1H), 4.43 (d, J = 4.8 Hz, 2H), 4.37-4.17 (m, 2H), 2.74 (d, J =0.9 Hz, 3H), 2.21 (s, 3H), 1.86 (s, 3H) 471

LCMS: 708.6 [M + H]+; 1H NMR (400 MHz, DMSO- d6); 1H NMR (400 MHz,DMSO-d6) δ 8.69 (d, J = 0.8 Hz, 1H), 8.30 (s, 1H), 8.11 (s, 1H),7.61-7.57 (m, 1H), 7.55 (d, J = 5.6 Hz, 1H), 7.45-7.42 (m, 2H), 7.36 (d,J = 9.0 Hz, 1H), 4.54-4.10 (m, 1H), 2.72 (s, 3H), 2.58 (d, J = 1.0 Hz,3H), 1.86 (s, 3H) 472

LCMS: 708.6 [M + H]+; 1H NMR (400 MHz, DMSO- d6) δ 8.54 (d, J = 4.8 Hz,1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.51(t, J = 5.1 Hz, 1H), 7.46-7.41 (m, 2H), 7.36 (d, J = 9.0 Hz, 1H),4.57-4.15 (m, 2H), 2.72 (s, 3H), 2.56 (d, J = 3.0 Hz, 3H), 1.87 (s, 3H)473

LCMS: 708.6 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.17(dt, J = 4.7, 1.4 Hz, 1H), 7.99 (s, 1H), 7.77 (ddd, J = 9.8, 8.3, 1.3Hz, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.45-7.40 (m, 2H), 7.36 (dt, J= 8.4, 1.9 Hz, 2H), 4.66 (s, 2H), 4.42 (t, J = 5.0 Hz, 2H), 4.26 (t, J =5.1 Hz, 2H), 2.70 (s, 3H), 1.86 (s, 3H) 483

MS (ESI) m/z 711.6 [M + 1]+; ; 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H),8.38 (s, 1H), 8.27 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.46-7.34(m, 3H), 4.43 (d, J = 5.3 Hz, 2H), 4.27 (s, 2H), 4.14 (s, 2H), 3.30 (d,J = 11.8 Hz, 2H), 2.77 (d, J = 20.8 Hz, 7H), 2.68 (s, 3H), 1.88 (s, 3H)484

MS (ESI) m/z 615.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J =1.7 Hz, 1H), 8.24 (s, 1H), 7.98-7.94 (m, 1H), 7.60 (dd, J = 8.9, 2.7 Hz,1H), 7.53 (s, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H),4.81 (s, 2H), 4.41 (t, J = 5.1 Hz, 2H), 4.25 (t, J = 5.1 Hz, 2H), 1.77(s, 3H) 485

MS (ESI) m/z 711.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H),8.22 (s, 1H), 7.96 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (d, J =2.5 Hz, 2H), 7.36 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 5.1 Hz, 2H), 4.26(d, J = 5.0 Hz, 2H), 3.95 (s, 2H), 3.38 (d, J = 11.4 Hz, 2H), 2.92 (d, J= 11.8 Hz, 4H), 2.78 (d, J = 4.5 Hz, 3H), 2.70 (s, 3H), 1.85 (s, 3H) 486

MS (ESI) m/z 711.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H),7.96 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (d, J = 2.5 Hz, 2H),7.36 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 5.0 Hz, 2H), 4.25 (t, J = 5.0 Hz,2H), 3.89 (s, 2H), 3.53 (s, 4H), 2.70 (s, 3H), 1.83 (s, 3H) 487

MS (ESI) m/z 791.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =5.0 Hz, 1H), 8.50 (s, 1H), 8.33 (d, J = 1.8 Hz, 1H), 7.96-7.93 (m, 1H),7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.49 (d, J = 5.0 Hz, 1H), 7.44 (d, J =2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.42 (t, J = 5.0 Hz, 2H), 4.26(t, J = 5.1 Hz, 2H), 2.61 (s, 4H), 1.86 (s, 3H) 489

MS (ESI) m/z 741.8 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H),8.21 (s, 1H), 7.97 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.48-7.41(m, 2H), 7.36 (d, J = 9.0 Hz, 1H), 4.74 (s, 2H), 4.41 (t, J = 5.0 Hz,2H), 4.25 (t, J = 5.0 Hz, 2H), 3.94 (s, 2H), 2.92 (d, J = 12.0 Hz, 5H),2.78 (d, J = 4.2 Hz, 3H), 1.77 (s, 3H) 494

MS (ESI) m/z 735.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.8 Hz, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H),7.51 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.0 Hz,1H), 4.42 (t, J = 4.9 Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H), 4.08- 3.82 (m,4H), 3.38 (d, J = 6.2 Hz, 2H), 3.16- 3.02 (m, 1H), 1.79 (s, 3H) 495

MS (ESI) m/z: 599.01; 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.36 (s,1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.59-7.56 (m, 1H), 7.37- 7.35 (m, 2H),4.48-4.44 (m, 1H), 4.27-4.20 (m, 3H), 2.08 (s, 3H), 1.17 (s, 3H) 496

MS (ESI) m/z 569.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H),8.34 (d, J = 4.28 Hz, 1H), 8.23 (s, 1H), 7.44 (dd, J = 8.80, 2.40 Hz,1H), 7.25 (d, J = 2.16 Hz, 1H), 7.21 (d, J = 8.84 Hz, 1H), 7.10 (s, 1H),4.41-4.29 (m, 4H), 4.08 (t, J = 8.48, 1H), 2.12-2.10 (m, 4H), 2.03 (s,3H) 501

MS (ESI) m/z 684.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.61 (dd, J = 8.92, 2.6 Hz,1H), 7.51 (d, J = 4.76 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.37 (d, J =9.00 Hz, 1H), 4.42 (t, J = 5.76 Hz, 2H), 4.26 (t, J = 4.36 Hz, 2H), 3.95(bs, 2H), 3.55 (bs, 4H), 2.56 (bs, 4H), 1.76 (s, 3H) 502

MS (ESI) m/z 697.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.76, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.61 (dd, J = 8.84, 2.56 Hz, 1H),7.48 (d, J = 4.76 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.00Hz, 1H), 4.42 (t, J = 3.8 Hz, 2H), 4.26 (t, J = 5.8, 2H), 3.94 (bs, 2H),3.40 (d, J = 10.68 Hz, 2H), 2.94 (d, J = 10.68 Hz, 4H), 2.79 (d, J = 3.4Hz, 3H), 2.50 (m, 2H), 1.77 (s, 3H) 503

MS (ESI) m/z 660.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J =4.68 Hz, 1H), 8.11 (s, 1H), 8.07 (s,1H), 7.63 (d, J = 8.36, 1H), 7.57(d, J = 11.32 Hz, 1H), 7.49 (d, J = 4.72 Hz, 1H), 4.63 (bs, 2H), 4.46(t, J = 4.64 Hz, 2H), 4.28 (t, J = 4.72 Hz, 2H), 2.89 (bs, 6H), 1.75 (s,3H) 505

MS (ESI) m/z 637.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J =4.76 Hz, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.63 (d, J = 8.32 Hz, 1H),7.55 (d, J = 11.2 Hz, 1H), 7.50 (d, J = 4.68 Hz, 1H), 4.43 (t, J = 5.00Hz, 2H), 4.26 (t, J = 4.44 Hz, 2H), 1.68 (s, 3H) 519

MS (ESI) m/z 696.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H),8.92 (d, J = 4.44 Hz, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.65- 7.54 (m,2H), 7.45 (d, J = 1.84 Hz, 1H), 7.36 (d, J = 8.84 Hz, 1H), 4.42 (t, J =4.68 Hz, 2H), 4.24 (t, J = 5.24 Hz, 2H), 3.56 (s, 3H), 1.65 (s, 3H) 521

MS (ESI) m/z 648.07 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H),8.84 (d, J = 4.80 Hz, 1H), 8.12 (s, 1H), 8.09 (S, 1H), 7.59 (dd, J =8.88, 2.80 1H), 7.46 (d, J = 4.76 Hz, 1H), 7.41 (d, J = 2.60 Hz,1H),7.34 (d, J = 9.04 Hz, 1H), 4.42-4.38 (m, 2H), 4.28-4.21 (m, 2H), 3.88(s, 3H), 1.66 (s, 3H) 522

MS (ESI) m/z 718.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.16 Hz, 1H), 8.27 (s, 1H), 8.98 (s, 1H), 7.59 (d, J = 8.52 Hz, 1H),7.50 (d, J = 4.4 Hz, 1H), 7.43 (s, 1H), 7.36 (d, J = 9.08 Hz, 1H), 4.41(bs, 2H), 4.24 (bs, 2H), 3.94 (s, 2H), 2.61 (s, 4H), 1.92 (s, 4H), 1.76(s, 3H) 523

MS (ESI) m/z 710.21 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.23 (bs,1H), 8.82 (d, J = 3.2 Hz, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.59 (d, J =8.88 Hz, 1H), 7.50-7.42 (m, 1H), 7.43 (s, 1H) 7.35 (d, J = 8.24 Hz, 1H),4.41 (s, 2H), 4.24 (s, 2H), 3.84 (s, 1H), 3.50-3.30 (m, 4H), 3.07 (s,2H), 2.02 (s, 2H), 1.85- 1.70 (m, 5H) 524

MS (ESI) m/z 616.13 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.27 (bs,1H), 8.82 (s, J = 4.72 Hz, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.58 (dd, J= 8.80, 2.44 Hz, 1H ), 7.46 (d, J = 4.76 Hz, 1H), 7.40 (d, J = 2.52 Hz,1H), 7.35 (d, J = 8.8 Hz, 1H), 5.52 (s, 2H), 4.40 (t, J = 4.28 Hz, 2H),4.23 (t, J = 5.2 Hz, 2H), 1.73 (s, 3H) 525

MS (ESI) m/z 692.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H),8.23 (s, 1H), 7.97 (s, 1H), 7.65-7.26 (m, 4H), 6.16 (t, J = 56.26 Hz,1H), 4.40 (s, 2H), 4.24 (s, 2H), 4.04 (s, 2H), 2.94 (t, J = 14.2 Hz,2H), 2.28 (s, 3H), 1.75 (s, 3H) 526

MS (ESI) m/z 668.20 [M + 1]+; 1H-NMR (400 MHz, CD3OD) δ 8.80 (d ,J =4.84 Hz, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 7.57 (dd, J = 2.96, 9.76 Hz,1H), 7.49 (d, J = 4.84 Hz, 1H), 7.36 (d, J = 2.36 Hz, 1H), 7.31 (d, J =8.88 Hz, 1H), 4.98 (s, 2H), 4.46 (t, J = 2.36, 2H), 4.37 (t, J = 4.6 Hz,2H),.3.74 (s, 4H), 2.20 (s, 4H), 2.03 (s, 3H) 527

MS (ESI) m/z 670.40 [M + 1]+; 1H-NMR (400 MHz CD3OD) δ 8.78 (d, J = 4.88Hz, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.57 (dd, J = 2.56, 8.92 Hz, 1H),7.49 (d, J = 4.92 Hz, 1H), 7.36 (d, J = 2.48 Hz, 1H), 7.32 (d, J = 8.84Hz, 1H), 4.98 (s, 2H), 4.46 (t, J = 4.76, 2H), 4.37 (t, J = 4.5 Hz,2H),.3.52-3.47 (m, 4H), 2.03 (s, 3H), 1.48-1.29 (m, 6H) 528

MS (ESI) m/z 682.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 + D20) δ 8.83 (d,J = 4.80 Hz, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.61-7.57 (dd, J = 2.48,8.80 Hz, 1H), 7.48 (d, J = 4.68 Hz, 1H), 7.44 (d, J = 2.48 Hz, 1H), 7.36(d, J = 8.92 Hz, 1H), 4.58 (m, 2H), 4.40 (t, J = 6.36 Hz, 2H), 4.26 (t,J = 4.52 Hz, 2H)., 3.29 (m, 4H), 1.75 (m, 7H), 1.54 (m, 2H) 535

MS (ESI) m/z 537.11 [M +1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.77 (bs, 1H),8.39 (s, 1H), 7.23 (s, 1H), 7.03 (d, J = 8.9 Hz), 6.92 (s, 1H), 4.51 (m,2H), 4.38 (t, J = 4.8 Hz, 3H), 4.19-4.16 (m, 2H), 3.95 (d, J = 11.2 Hz,1H), 3.63-3.59 (m, 1H), 3.27 (d, J = 9.6 Hz, 1H), 2.94-2.79 (m, 5H) 549

MS (ESI) m/z 651.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.72 Hz, 1H), 8.22 (s, 1H), 8.07 (s, 1H), 7.61-7.23 (m, 5H), 4.41 (t, J= 4.2 Hz, 2H), 4.26 (t, J = 4.2 Hz, 2H), 1.72 (s, 3H) 553

MS (ESI) m/z 636.0 [M + 1]+;; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J =4.7 Hz, 1H), 8.53 (s, 1H), 8.21 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.7(d, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J = 4.7 Hz, 1H), 4.91 (s,2H), 4.63 (bs, 2H), 2.87 (bs, 6H), 2.11 (s, 3H) 554

MS (ESI) m/z 613.04 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.7(d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.55 (d, J = 4.7 Hz, 1H), 4.88 (s,2H), 2.07 (s, 3H) 555

MS (ESI) m/z 633. [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J =4.88, 1H), 8.089 (s, 1H), 7.615 (dd, J = 8.92, 8.96, 1H), 7.519 (d, J =4.88 Hz, 1H), 7.414 (d, J = 2.6, 1H), 7.37 (d, J = 8.96 Hz, 1H), 4.43(bs, 2H), 4.29 (bs, 2H), 2.41 (s, 3H), 1.89 (s, 3H) 556

MS (ESI) m/z 656.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =4.76, 1H), 8.088 (s,1H), 7.618 (dd, J = 8.84, 8.72, 1H), 7.517 (d, J =4.84 Hz, 1H), 7.44 (d, J = 2.16, 1H), 7.36 (d, J = 8.88 Hz, 1H), 4.602(bs, 2H), 4.419 (bs, 2H), 4.28 (bs, 2H), 2.84 (bs, 6H), 2.34 (s, 3H),1.83 (s, 3H) 558

MS (ESI) m/z 633.10 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.24 (s ,1H),8.03 (s, 1H), 7.61-7.58 (dd, J = 2.52,J = 8.84 Hz, 1H), 7.44 (s,1H),-7.41 (d, J = 2.52, 1H),7.37 (d, J = 8.92, 1H), 4.42 (t, J = 5.46Hz, 2H), 4.27 (t, J = 4.32 Hz, 2H), 2.71 (s, 3H),1.79 (s, 3H) 559

MS (ESI) m/z 656.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.48 (s, 1H),8.06 (bs, 1H), 8.03 (s, 1H), 7.62 (dd, J = 8.92 Hz, 2.52 Hz, 1 H),7.45-7.34 (m, 2 H), 7.36 (d, J = 8.32 Hz, 1H), 4.75 (s, 2 H), 4.44 (t, J= 3.6 Hz, 2H), 4.29 (t, J = 5.6 Hz, 2 H), 2.99 (s, 6H), 2.72 (s, 3H),1.82 (s, 3 H) 560

MS (ESI) m/z: 593 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H),8.59 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 7.75 (d, J = 8.24 Hz, 1H),7.68-7.64 (m, 2H), 7.46 (s, 1H), 4.87 (s, 2H), 2.59 (s, 3H), 2.14 (s,3H) 561

MS (ESI) m/z 627.06 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) 13.23 (bs, 1H),8.54 (s, 1H), 8.20 (s, 1H), 7.75 (d, J = 8.32 Hz, 1H), 7.69 (dd, J =8.24, 1.96 Hz, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 4.87 (s, 2H). 2.64 (s,3H), 2.14 (s 3H) 562

MS (ESI) m/z 650.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.34 (bs,1H), 8.73 (d, J = 4.7 Hz, 1H), 8.66 (s, 1H), 8.13 (d, J = 9.7 Hz, 1H),7.76 (d, J = 9.0 Hz, 1H), 7.68 (m, 1H), 7.53 (d, J = 4.7 Hz, 1H), 7.37(t, J = 53.7 Hz, 1H), 4.88 (s, 2H), 2.22 (s, 3H) 563

MS (ESI) m/z 635.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (bs,1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.67 (s, 1H), 7.60 (dd, J= 1.68, 8.56 Hz, 1H), 7.45 (bs, 1H), 7.35 (d, J = 8.88 Hz, 1H), 7.18 (t,J = 54.84 Hz, 1H), 4.39-4.35 (m, 2H), 4.23-4.20 (m, 2H), 1.67 (s, 3H)564

MS (ESI) m/z 655.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H),9.45 (s, 1H), 8.18 (s, 1H), 7.50 (dd, J = 2.52 Hz, J = 9.12 Hz, 2H),7.28-7.25 (m, 2H), 7.15 (d, J = 7.28 Hz, 1H), 4.75 (s, 2H), 4.36 (bs,2H), 4.24 (bs, 2H), 2.98 (s, 6H), 2.68 (s, 3H), 1.72 (s, 3H) 565

MS (ESI) m/z 676.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.02 (bs,1H), 8.38 (s, 1H), 8.35 (s, 1H), 7.60 (dd, J = 8.80, 2.40 Hz, 1H), 7.47(s, 1H), 7.42 (d, J = 2.48 Hz, 1H), 7.35 (d, J = 8.16 Hz, 1H), 4.41 (t,J = 5.0 Hz, 2H), 4. 24 (t, J = 4.72 Hz, 2H), 3.56 (s, 3H), 2.68 (s, 3H),1.78 (s, 3H) 568

MS (ESI) m/z 733.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H),8.32 (s, 1H), 7.97 (s, 1H), 7.61-7.59 (m, 1H), 7.48 (s, 1H), 7.43 (s,1H), 7.36 (d, J = 8.8 Hz, 1H), 4.41 (s, 2H), 4.23 (bs, 2H), 3.77 (bs,2H), 3.55 (s, 3H), 2.69 (s, 3H), 2.22 (s, 6H), 1.75 (s, 3H) 569

MS (ESI) m/z 662.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H),8.89 (d, J = 4.76 Hz, 1H), 8.39 (s, 2H), 8.02 (s, 1H), 7.63- 7.60 (dd, J= 2.56, 2.44 Hz 1H), 7.56 (d, J = 4.72 Hz, 1H), 7.46 (d, J = 2.44 Hz,1H), 7.36 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 4.4 Hz, 2H), 4.24 (t, J =3.86 Hz, 2H), 3.56 (s, 3H), 1.73 (s, 3H) 571

MS (ESI) m/z 617.11 [M + 1]+; 1H NMR (400 MHz, MeOD) δ 8.31 (s, 1H),8.16 (s, 1H), 8.00 (s, 1H), 7.56 (s, 1H),7.51 (d, J = 8.08 Hz, 1H), 7.34(d, J = 10.84 Hz, 1H), 4.50 (t, J = 4.80 Hz, 2H), 4.38 (t, J = 5.20 Hz,2H), 2.96 (s, 3H), 2.03 (s, 3H) 589

MS (ESI) m/z 617.11 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H),8.36 (d, J = 5.64 Hz, 1H), 7.60 (dd, J = 8.88, 2.64 Hz, 1H), 7.43-7.39(m, 2H), 7.36 (d, J = 9.00 Hz, 1H), 4.42 (t, J = 4.52 Hz, 2H), 4.28 (t,J = 4.76 Hz, 2H), 2.69 (s, 3H), 1.94 (s, 3H) 590

MS (ESI) m/z 615.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H),7.95-7.93 (m, 3H), 7.57 (dd, J = 2.56, 8.92 Hz, 1H), 7.39 (d, J = 2.52Hz, 1H), 7.33 (d, J = 9.04 Hz, 1H), 4.39 (t, J = 4.48 Hz, 2H), 4.30 (t,J = 4.36 Hz, 2H), 3.69 (s, 3H), 2.10 (s, 3H) 591

MS (ESI) m/z 612.91 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 14.09 (bs,1H), 68.77 (d, J = 4.56 Hz, 1H), 8.37 (s, 1H), 7.97 (s, 1H), 7.59 (d, J= 8.48 Hz, 1H), 7.50 (d, J = 4.56 Hz, 1H), 7.42 (bs, 1H), 7.35 (d, J =8.84 Hz, 1H), 4.42 (t, J = 4.32 Hz, 2H), 4.26 (t, J = 3.20 Hz, 2H),2.85-2.79 (m, 2H), 1.85 (s, 3H), 0.97 (t, J = 7.24 Hz, 3H) 595

MS (ESI) m/z 629.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.37-8.28 (m,2H), 7.61 (s, 1H), 7.48-7.43 (m, 1H), 7.31-7.26 (m, 2H), 7.05 (bs, 1H),4.33 (bs, 2H), 4.24 (bs, 2H), 3.81 (s, 2H), 3.01 (s, 2H), 1.80 (s, 3H)605

MS (ESI) m/z 615.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H),8.16 (s, 1H), 7.52 (d, J = 7.44, 1H), 7.36 (s, 1H), 7.29 (d, J = 9.04Hz, 1H), 6.54 (s, 1H), 6.30 (s, 1H), 4.88 (s, 2H), 4.38 (s, 2H), 4.31(s, 2H), 2.32 (s, 3H) 610

MS (ESI) m/z 670.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H),7.93 (s, 1H), 7.59 (dd, J = 8.68, 2.16 Hz, 1H), 7.41-7.34 (m, 3H), 4.40(t, J = 4.76 Hz, 2H), 4.24 (t, J = 4.68 Hz, 2H), 3.20 (d, J = 7.48 Hz,2H), 2.69 (s, 3H), 2.57 (d, J = 10.48 Hz, 2H), 2.28 (s, 6H), 1.83 (s,3H) 614

MS (ESI) m/z 617.06 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H),8.14 (bs, 2H), 7.74 (t, J = 8.56 Hz, 1H), 7.29 (bs, 1H), 7.20 (d, J =9.08 Hz, 1H), 4.41 (bs, 1H), 4.36 (bs, 1H), 4.23 (s, 2H), 2.66 (s, 3H),1.70 (s, 3H) 615

MS (ESI) m/z 691.19 [M + 1]+; ; 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J =4.72 Hz, 1H), 8.48 (s, 1H), 8.06 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66(d, J = 7.1 Hz, 1H), 7.57 (s, 1H), 7.47 (d, J = 4.64, 1H), 4.78 (s, 2H),3.95 (s, 2H), 3.37 (d, J = 12.5 Hz, 2H), 2.97 (d, J = 10.68 Hz, 4H),2.75 (s, 3H), 2.58-2.56 (m, 2H), 2.1 (s, 3H) 616

MS (ESI) m/z 705.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H),9.43 (s, 1H), 8.54 (s, 1H), 8.11 (s, 1H), 7.75 (d, J = 8.32 Hz, 1H),7.69 (dd, J = 8.36, 6.2 Hz, 1H), 7.65 (d, J = 1.96 Hz, 1H), 7.47 (s,1H), 4.87 (s, 2H), 3.97 (s, 2H), 2.95 (d, J = 10.08 Hz, 4H), 2.80 (s,3H), 2.66 (s, 3H), 2.62 (s, 4H), 2.17 (s, 3H) 617

MS (ESI) m/z 678.16 [M + 1]+; ; 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J =4.76 Hz, 1H), 8.6 (s, 1H), 8.1 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.69(d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.55 (d, J = 4.76 Hz, 1H), 4.88 (s,2H), 3.97 (s, 2H), 3.56 (s, 4H), 2.58 (s, 4H), 2.13 (s, 3H) 629

MS (ESI) m/z 676.18 [M + 1]+; ; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J =5.56 Hz, 2H), 8.25 (s, 1H), 8.09 (s, 1H), 7.59 (dd, J = 7.56 Hz, 2.64Hz, 1H), 7.53 (d, J = 4.88 Hz, 2H), 7.42-7.40 (m, 2H), 7.36 (d, J = 8.92Hz, 1H), 4.41 (t, J = 4.76 Hz ,2H), 4.28 (t, J = 4.36 Hz, 2H), 2.72 (s,3H), 1.86 (s, 3H) 630

MS (ESI) m/z 676.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =3.7, 1H), 8.69 (s, 1H), 8.31 (s, 1H), 8.05 (s,1H), 7.99 (d, J = 7.8 Hz,1H), 7.66- 7.58 (m, 2H), 7.45 (s, 1H), 7.424 (d, J = 2.56 Hz, 1H), 7.36(d, J = 8.9, 1H), 4.42 (t, J = 9.2 Hz, 2H), 4.28 (t, J = 9.6 Hz, 2H),2.73 (s, 3H), 1.87 (s, 3H) 631

MS (ESI) m/z 676.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J =4.7 Hz, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 8.03 (t, J = 7.8 Hz, 1H), 7.68(d, J = 7.6 Hz, 1H), 7.61-7.52 (m, 2H), 7.43 (s, 2H), 7.36 (d, J = 8.9Hz, 1H), 4.40 (s, 2H), 4.26 (s, 2H), 2.72 (s, 3H), 1.83 (s, 3H) 632

MS (ESI) m/z 665.30 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6), 13.51 (bs, 1H),8.26 (s ,1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.60 (dd, J = 2.36, 8.88 Hz,1H), 7.52 (s, 1H), 7.44 (s, 1H),7.42 (d, J = 2.52 Hz, 1H), 7.37 (d, J =8.88 Hz, 1H), 7.19 (s, 1H), 4.42 (t, J = 5.28 Hz, 2H), 4.28 (t, J = 4.24Hz, 2H), 2.73 (s, 3H), 1.87 (s, 3H) 633

MS (ESI) m/z 665.23 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) 8.35 (s ,1H),8.19 (d, J = 2.08 Hz,1H), 8.11 (s, 1H), 7.87 (d, J = 1.52 Hz, 1H),7.61-7.58 (dd, J = 2.64, 8.88 Hz, 1H), 7.44- 7.42 (m, 2H), 7.37 (d, J =8.88 Hz, 1H), 6.63 (t, J = 2.24 Hz, 1H), 4.41 (t, J = 4.52 Hz, 2H), 4.28(t, J = 4.12 Hz, 2H), 2.72 (s, 3H), 1.84 (s, 3H) 634

MS (ESI) m/z 697.13 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.51 (bs,1H), 9.75 (bs, 1H), 8.23 (s, 1H), 7.92 (s, 1H), 7.61-7.58 (t, J = 6.5Hz, 1H), 7.42-7.41 (t, J = 6.5 Hz, 2H), 7.37 (d, J = 8.9 Hz, 1H), 4.40(t, J = 6.2 Hz, 2H), 4.24 (t, J = 6.1 Hz, 2H), 3.83 (m, 2H), 3.49 (m,2H), 3.24 (m, 2H), 3.03 (m, 2H), 2.28 (s, 3H), 2.71 (s, 3H), 1.82 (s,3H) 636

MS (ESI) m/z 642.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.87 (bs,1H), 9.92 (s, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.62 (dd, J= 2.40, 8.8 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J = 3.28 Hz, 1H), 7.37 (d, J= 8.92 Hz, 1H), 4.63 (bs, 2H), 4.43 (t, J = 4.84 Hz, 2H), 4.26 (t, J =4.64 Hz, 2H), 2.96 (s, 6H), 1.76 (s, 3H 637

MS (ESI) m/z 725.09 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.18 (s,1H),7.94 (s, 1H), 7.61-7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.46 (s, 1H), 7.44(d, J = 2.48 Hz, 1H), 7.36 (d, J = 8.96 Hz, 1H), 4.41 (t, J = 5.2 Hz,2H), 4.24 (t, J = 5.2 Hz, 2H), 3.94 (s, 2H), 3.40-3.37 (m, 2H),3.04-2.98 (m, 2H), 2.92 (m, 4H), 2.78 (d, J = 3.52 Hz, 3H), 2.54 (m,2H), 1.80 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H) 638

MS (ESI) m/z 727.07 [M + 1]+; ; 1H NMR (400 MHz, DMSO-d6) δ 12.7 (bs,1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.59-7.56 (dd, J = 2.8, 9.2 Hz, 1H),7.40 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.90 (s, 1H), 4.41(t, J = 6.4 Hz, 2H), 4.28 (t, J = 5.6 Hz, 2H), 4.07 (s, 3H), 3.94 (s,2H), 3.39 (d, J = 11.2 Hz, 2H), 2.91 (d, J = 11.2 Hz, 4H), 2.78 (d, J =3.2 Hz, 2H), 2.56 (d, J = 7.6 Hz, 2H), 1.88 (s, 3H) 640

MS (ESI) m/z 751.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.9 Hz, 1H), 8.32 (s, 1H), 7.93 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H),7.53 (d, J = 4.9 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.0 Hz,1H), 4.41 (t, J = 4.9 Hz, 2H), 4.24 (t, J = 5.0 Hz, 2H), 3.31 (q, J =10.1 Hz, 2H), 3.07-2.58 (m, 6H), 1.75 (s, 3H). Note: piperazine protonswere very broad and could not be properly integrated 641

MS (ESI) m/z 642.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J =4.92 Hz, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.61 (dd, J = 8.6, 2.4 Hz,1H), 7.47 (m, 2H), 7.37 (d, J = 9 Hz, 1H), 4.67 (s, 2H), 4.41 (t, J =5.28 Hz, 2H), 4.25 (t, J = 4.28 Hz, 2H), 2.88 (s, 6H), 2.53 (s, 3H) 642

MS (ESI) m/z 726.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.44 (bs,1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.59 (dd, J = 8.8, 2.5 Hz, 1H),7.42-7.41 (m, 2H), 7.35 (d, J = 8.9 Hz, 1H), 4.4 (t, J = 5.9 Hz, 2H),4.24 (t, J = 5.6 Hz, 2H), 3.83 (s, 2H), 3.47-3.43 (m, 2H), 2.68 (s, 3H),2.62 (d, J = 10.5 Hz, 2H), 1.89 (d, J = 6.2 Hz, 2H), 1.86 (s, 3H), 1.01(d, J = 6.2 Hz, 6H) 643

MS (ESI) m/z 705.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J =4.84 Hz, 1H), 8.05 (s, 1H), 7.75 (d, J = 8.20 Hz, 1H), 7.69 (d, J = 8.48Hz, 1H), 7.65 (s, 1H), 7.57 (d, J = 4.76 Hz, 1H), 4.88 (s, 2H), 3.86 (s,2H), 2.50- 2.32 (m, 8H, merged with moisture peak in DMSO), 2.17 (s,3H), 2.10 (s, 3H), 1.23 (s, 3H) 644

MS (ESI) m/z 743.07 [M + 1]+.;; 1H NMR (400 MHz, DMSO-d6) δ 13.2 (bs,1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.62-7.59 (dd, J = 2.4, 8.8 Hz, 1H),7.59 (s, 1H), 7.43 (d, J = 2.4 Hz, 1H ), 7.37 (d, J = 8.8 Hz, 1H), 4.99(t, J = 6.0 Hz, 1H), 4.87 (t, J = 6.0 Hz, 1H), 4.42 (t, J = 6.4 Hz, 2H),4.26 (t, J = 6.8 Hz, 2H), 3.94 (s, 2H), 3.45 (t, J = 6.0 Hz, 2H), 2.93(m, 4H), 2.78 (s, 3H), 2.50 (m, 2H), 1.76 (s, 3H) 645

MS (ESI) m/z 729.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.04 (bs,1H), 9.40 (s, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.60 (dd, J = 2.28, 8.72Hz, 1H), 7.53 (bs, 1H), 7.44 (d, J = 2.32 Hz, 1H), 7.36 (d, J = 8.92 Hz,1H), 5.76-5.65 (d, J = 46.8 Hz, 2H), 4.41 (t, J = 5.16 Hz, 2H), 4.25 (t,J = 5.72 Hz, 2H), 3.94 (s, 2H), 3.40-3.37 (m, 2H), 2.93-2.90 (m, 4H),2.79 (d, J = 3.32 Hz, 3H), 2.56-2.54 (m, 2H), 1.77 (s, 3H) 649

MS (ESI) m/z 697.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (bs, 2H),8.22 (s, 1H), 7.59 (s, 1H), 7.61 (dd, J = 2.76, 8.64 Hz, 1H), 7.42 (s,2H), 7.37 (d, J = 9.0, 1H), 4.42 (t, J = 4.44 Hz, 2H), 4.26 (t, J = 4.96Hz, 2H), 3.93 (s, 2H), 3.07 (s, 4H), 2.70 (m, 6H ), 1.84 (s , 3H) 652

MS (ESI) m/z 667.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H),7.93 (s, 1H), 7.61 (dd, J = 2.56 Hz, 8.8 Hz, 1H), 7.41 (s, 2H), 7.37 (d,J = 9.0 Hz, 1H ), 4.39 (m, 2H), 4.26 (m, 3H), 3.96 (bs, 2H), 3.55 (bs,2H), 2.70 (s, 3H), 2.35 (s, 3H), 1.85 (s, 3H) 655

MS (ESI) m/z 715.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.0 Hz,1H), 4.89 (dt, J = 47.3, 4.5 Hz, 2H), 4.41 (t, J = 5.0 Hz, 2H), 4.25 (t,J = 5.0 Hz, 2H), 4.03-3.88 (m, 2H), 3.74-3.09 (m, 8H), 1.77 (s, 3H) 660

LCMS (ESI) m/z 553.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J =2.1 Hz, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.31 (dd, J = 1.8, 0.7 Hz, 1H),8.23 (t, J = 2.1 Hz, 1H), 7.80 (dd, J = 1.7, 0.8 Hz, 1H), 7.50-7.39 (m,2H), 7.26 (d, J = 8.9 Hz, 1H), 4.43-4.31 (m, 4H), 2.11 (s, 3H) 661

LCMS (ESI) m/z 569.1 [M + 1+9-; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.3 Hz, 1H), 8.37-8.31 (m, 1H), 8.07 (dt, J = 1.7, 0.8 Hz, 1H), 7.98 (s,1H), 7.64-7.47 (m, 3H), 7.29 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 4.2 Hz,1H), 4.35 (t, J = 5.0 Hz, 2H), 4.21 (t, J = 4.9 Hz, 2H), 1.79 (s, 3H)662

LCMS (ESI) m/z 553.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.71 (dd, J =5.0, 0.8 Hz, 1H), 8.34- 8.28 (m, 1H), 8.05 (dd, J = 1.7, 0.8 Hz, 1H),7.88 (dd, J = 1.8, 0.8 Hz, 1H), 7.57 (dd, J = 5.0, 1.7 Hz, 1H),7.52-7.40 (m, 2H), 7.26 (d, J = 8.9 Hz, 1H), 4.44-4.31 (m, 4H), 2.96 (s,3H), 2.13 (s, 3H).5 (t, J = 4.7 Hz, 2H), 1.69 (s, 3H) 663

LCMS (ESI) m/z 557.0 [M + 1]+1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J =4.7 Hz, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.51 (dd, J = 8.9, 2.7 Hz, 1H),7.33 (d, J = 2.6 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 4.4 Hz,1H), 6.32 (d, J = 1.6 Hz, 1H), 4.34 (s, 2H), 4.23 (s, 2H), 1.81 (s, 3H)664

LCMS (ESI) m/z 615.0 [M + 1]+1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J =1.9 Hz, 1H), 8.35 (d, J = 1.9 Hz, 1H), 8.32-8.28 (m, 1H), 8.01 (dd, J =1.7, 0.8 Hz, 1H), 7.49-7.40 (m, 2H), 7.25 (dd, J = 8.6, 0.6 Hz, 1H),4.36 (dd, J = 11.4, 4.4 Hz, 4H), 3.85 (s, 3H), 2.19 (s, 3H) 666

LCMS (ESI) m/z 653.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J =4.7 Hz, 1H), 8.38-8.32 (m, 1H), 8.17-8.05 (m, 1H), 7.61- 7.51 (m, 2H),7.42 (d, J = 2.6 Hz, 1H), 7.32 667

LCMS (ESI) m/z 627.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =5.0 Hz, 1H), 8.35 (dd, J = 1.7, 0.6 Hz, 1H), 7.97 (dt, J = 1.7, 0.8 Hz,1H), 7.57 (dd, J = 8.9, 2.7 Hz, 1H), 7.49 (d, J = 5.0 Hz, 1H), 7.42 (d,J = 2.6 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 4.37 (t, J = 5.0 Hz, 1H),4.23 (t, J = 5.1 Hz, 1H), 3.85 (q, J = 6.8 Hz, OH), 1.83 (s, 2H), 0.99(d, J = 6.8 Hz, 3H) 668

LCMS (ESI) m/z 613.3 [M + 1+9-; 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J =1.7 Hz, 1H), 7.93 (dt, J = 1.7, 0.8 Hz, 1H), 7.56 (dd, J = 8.9, 2.7 Hz,1H), 7.42-7.29 (m, 2H), 4.39 (t, J = 5.0 Hz, 1H), 4.24 (t, J = 5.0 Hz,1H), 2.66 (s, 2H), 2.35 (s, 2H), 1.92 (s, 2H) 670

LCMS (ESI) m/z 670.2 [M + 1+9-; 1H NMR (400 MHz, DMSO-d6) δ 7.57 (dd, J= 8.9, 2.7 Hz, 1H), 7.43- 7.36 (m, 2H), 7.32 (d, J = 9.0 Hz, 1H), 4.38(t, J = 4.9 Hz, 2H), 2.67 (s, 4H), 2.32 (s, 3H), 1.87 (s, 3H) 672

LCMS (ESI) m/z 625.9 [M + 1+9-; 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J =1.7 Hz, 1H), 8.17 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.56 (dd, J = 8.9,2.7 Hz, 1H), 7.44-7.38 (m, 2H), 7.32 (d, J = 9.0 Hz, 1H), 4.36 (t, J =5.1 Hz, 2H), 4.23 t, J = 5.1 Hz, 2H), 1.78 (s, 3H) 675

LCMS (ESI) m/z 690.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H),8.03 (s, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H),7.46-7.36 (m, 5H), 7.33 (d, J = 9.0 Hz, 1H), 4.37 (s, 2H), 4.24 (s, 2H),2.69 (s, 3H), 2.50 (s, 4H), 1.80 (s, 3H) 684

LCMS (ESI) m/z 708.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H),8.06 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.56 (dd, J = 9.3, 2.3 Hz,1H), 7.43 (dd, J = 6.7, 4.0 Hz, 3H), 7.36 (d, J = 9.0 Hz, 1H), 4.41 (bs,2H), 4.28 (bs, 2H), 2.73 (s, 3H), 2.56 (s, 3H), 1.85 (s, 3H) 686

LCMS (ESI) m/z 704.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J =5.4 Hz, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.57 (dd, J = 8.9, 2.7 Hz, 1H),7.50-7.38 (m, 3H), 7.33 (d, J = 9.0 Hz, 1H), 4.39 (m, 2H), 4.25 (m 2H),2.70 (s, 3H), 2.61 (s, 3H), 2.00 (s, 3H), 1.81 (s, 3H) 687

LCMS (ESI) m/z 690.2 [M + 1+9-; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s,1H), 7.85 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.41(d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.86 (t, J = 12.5 Hz,4H), 4.39 (t, J = 5.0 Hz, 2H), 4.22 (t, J = 5.0 Hz, 2H), 2.72 (s, 3H),1.79 (s, 3H) 705

MS (ESI) m/z 639.0 [M + 1]+; 1H-NMR (400 MHz, d6- DMSO) δ/ppm =9.81-9.70 (b, 1H), 8.63 (d, J = 4.7 Hz, 1H), 8.09 (s, 1H), 7.72 (d, J =5.4 Hz, 1H), 7.56 (dd, J = 8.9, 2.6 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H),7.37 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 4.7 Hz,1H), 4.38 (t, J = 4.9 Hz, 2H), 4.27 (t, J = 4.9 Hz, 2H), 3.92-3.82 (m,2H), 3.59- 3.50 (m, 2H), 3.30-3.20 (m, 2H), 3.14-3.01 (m, 2H), 2.91 (bs,3H), 1.90 (s, 3H) 706

MS (ESI) m/z 650.8 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.71-8.64 (m,2H), 8.29 (d, J = 0.6 Hz, 1H), 7.90 (dd, J = 9.2, 3.0 Hz, 1H), 7.78 (d,J = 5.6 Hz, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.48 (d, J = 5.5 Hz,1H), 7.41 (d, J = 2.7 Hz, 1H), 7.33 (d, J = 8.9 Hz, 1H), 7.26 (d, J =4.7 Hz, 1H), 4.43-4.35 (m, 2H), 4.34-4.15 (m, 1H), 2.19 (d, J = 1.0 Hz,3H), 1.88 (s, 3H) 708

MS (ESI) m/z 682.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.90 (s, 1H), 7.63-7.56 (m, 1H), 7.46-7.38 (m, 2H), 7.35 (d, J = 8.96Hz, 1H), 4.49-4.32 (m, 2H), 4.31-4.18 (m, 2H), 3.70-3.66 (m, 1H),3.26-3.22 (m, 2H), 2.69 (s, 3H), 2.32-2.22 (m, 2H), 2.22-2.09 (m, 2H),2.07 (s, 3H), 1.80 (s, 3H) 709

MS (ESI) m/z 684.07 [M + 1+9-; 1H NMR (400 MHz, DMSO-d6) 8.23 (s, 1H),7.94 (s, 1H), 7.60 (dd, J = 8.80, 2.40 Hz, 1H), 7.44-7.38 (m, 2H), 7.36(d, J = 8.96 Hz, 1H), 4.40 (t, J = 4.76 Hz, 2H), 4.25 (t, J = 4.24 Hz,2H), 3.05-3.01 (m, 4H), 2.69 (s, 3H), 2.50-2.30 (m, 6H), 1.91- 1.78 (m,5H) 711

MS (ESI) m/z 670.05 [M + 1+9-; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.89 (s, 1H), 7.59 (dd, J = 8.80, 2.40, 1H), 7.45-7.40 (m, 2H), 7.35 (d,J = 8.84 Hz, 1H), 4.39 (t, J = 5.40 Hz, 2H),), 4.30-4.22 (m, 2H)3.72-3.67 (m, 1H), 2.70 (s, 3H), 2.16 (s, 6H), 1.80 (s, 3H), 1.55 (d, J= 6.68 Hz, 3H) 713

MS (ESI) m/z 710.17 [M + 1+9-; 1H NMR (400 MHz, DMSO-d6-FD20) δ 9.18(bs, 1H), 8.20 (s, 1H), 7.97 (s, 1H), 7.61-7.58 (dd, J = 2.4, 8.8 Hz,1H), 7.43 (s, 1H), 7.37 (d, J = 9.2 Hz, 1H), 4.42 (t, J = 5.6 Hz, 2H),4.26 (t, J = 3.6 Hz, 2H), 3.43 (bs, 3H), 3.06 (d, J = 6.8 Hz, 2H),2.92-2.86 (m, 2H), 2.73-2.70 (m, 3H), 2.02 (bs, 1H), 1.83-1.78 (m, 5H),1.63-1.54 (m, 2H) 714

MS (ESI) m/z 696.11 [M + 1+9-; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (bs,1H), 8.19-8.15 (m, 2H), 7.97 (s, 1H), 7.61-7.58 (dd, J = 2.8, 9.2 Hz,1H), 7.43- 7.42 (m, 2H), 7.37 (d, J = 8.8 Hz, 1H), 4.42 (t, J = 4.8 Hz,2H), 4.26 (t, J = 4.4 Hz, 2H), 3.29 (d, J = 11.2 Hz, 2H), 3.06 (d, J =11.2 Hz, 2H), 2.83-2.78 (m, 2H), 2.70 (s, 3H), 2.11-2.01 (m, 1H), 1.82(s, 3H), 1.75 (d, J = 12.4 Hz, 2H), 1.59-1.50 (m, 2H) 717

MS (ESI) m/z 621.98 [M + 1+9-; 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J =4.76 Hz, 1H), 8.65 (s, 1H), 8.30 (bs, 2H), 7.75 (d, J = 8.32, 1H), 7.69(m, 2H), 7.54 (d, J = 4.72 Hz, 1H), 4.85 (s, 2H), 4.48 (s, 2H), 2.77 (s,6H) 719

MS (ESI) m/z 710.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H),8.10 (s, 1H), 7.65 (s, 1H), 7.49 (dd, J = 8.76, 2.48 Hz, 1H), 7.28-7.24(m, 3H), 7.13 (d, J = 7.32 Hz, 1H), 4.34 (t, J = 5.16 Hz, 2H), 4.22 (t,J = 5.12 Hz, 2H), 3.93 (s, 2H), 3.37 (d, J = 11.32, 2H,), 3.33- 3.29 (m,2H, merged with moisture peak in DMSO), 2.90-2.88 (m, 4H), 2.78 (s, 3H),2.67 (s, 3H), 1.72 (s, 3H) 735

MS (ESI) m/z 690.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J =3.72 Hz, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.86 (d, J = 7.76 Hz, 1H),7.60 (dd, J = 2.52, 8.84 Hz, 1H), 7.50 (d, J = 4.96 Hz, 1H), 7.48 (s,1H), 7.44 (d, J = 2.6 Hz, 1H), 7.38 (d, J = 8.92 Hz, 1H), 4.43 (t, J =6.12 Hz, 2H), 4.27 (t, J = 5.32, 2H), 2.73 (s, 3H), 2.24 (s, 3H), 1.84(s, 3H) 736

MS (ESI) m/z 690.04 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J =4.0 Hz, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.60 (dd, J =8.8, 2.5 Hz, 1H), 7.56 (d, J = 5 Hz, 1H), 7.46 (s, 1H), 7.45 (d, J = 2.5Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 4.43 (bs, 2H), 4.28- 4.26 (m, 2H),2.73 (s, 3H), 2.11 (s, 3H), 1.84 (s, 3H) 738

MS (ESI) m/z 753.46 [M + 1]+.; 1H-NMR (400 MHz, CD3OD) δ 13.50 (bs, 1H),8.94 (t, J = 8.44 Hz, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.57 (dd, J =2.25, 8.88 Hz, 1H),7.42 (s, 1H), 7.36 (d, J = 8.80 Hz, 1H), 4.41 (t, J =4.32 Hz, 2H), 4.25 (t, J = 3.24 Hz, 2H), 3.96 (s, 2H),.3.50 (d, J =10.48 Hz, 2H), 2.95 (d, J = 11.64 Hz, 2H), 2.82 (d, J = 10.52 Hz, 2H),2.70 (s, 3H), 2.65 (d, J = 11.68 Hz, 2H), 1.85 (s, 3H), 1.30 (s, 9H) 739

MS (ESI) m/z 761.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H),7.96 (s, 1H), 7.60 (dd, J = 2.44, 8.88 Hz, 1H), 7.43 (s, 1H), 7.42 (s,1H), 7.36 (d, J = 8.96 Hz, 1H), 6.58-6.31 (m, 1H), 4.41 (t, J = 4.56 Hz,2H), 4.25 (t, J = 4.64 Hz, 2H), 3.95 (bs, 2H), 3.60-3.45 (m, 2H),3.32-3.11 (m, 4H), 2.77-2.72 (m, 4H), 2.70 (s, 3H), 1.83 (s, 3H) 740

MS (ESI) m/z 737.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.61 (bs,1H), 9.01 (bs, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.59 (dd, J = 8.88, 2.56Hz, 1H), 7.42 (s, 2H), 7.37 (d, J = 8.96 Hz, 1H), 4.41 (t, J = 4.16 Hz,2H), 4.25 (t, J = 4.96 Hz, 2H), 3.93 (s, 2H), 3.43 (s, 2H), 3.32-3.29(m, 2H), 2.98-2.88 (m, 2H), 2.72 (d, J = 3.60, 3H), 2.69 (s, 3H),2.18-2.16 (m, 2H), 1.91 (d, J = 8.2 Hz, 2H), 1.84 (s, 3H) 747

MS (ESI) m/z 690.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H),8.30 (d, J = 10.6 Hz, 1H), 8.07 (t, J = 9.7 Hz, 2H), 7.66 (bs, 1H), 7.57(s, 2H), 7.44 (bs, 2H), 7.36-7.29 (m, 1H), 4.39 (bs, 2H), 4.26 (bs, 2H),3.02 (bs, 2H), 1.77 (d, J = 11.0 Hz, 3H), 1.35 (s, 3H) 751

MS (ESI) m/z 693.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H),8.71 (d, J = 4.6 Hz, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.72 (t, J = 10.4Hz, 1H), 7.60 (dd, J = 8.84, 2.28 Hz, 1H), 7.45-7.35 (m, 2H), 7.36 (d, J= 8.9 Hz, 1H), 4.44-4.24 (m, 4H), 2.72 (s, 3H), 1.87 (s, 3H) 753

MS (ESI) m/z 629.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 16.55 (s, 1H),8.00-7.83 (m, 3H), 7.60-7.52 (m, 1H), 7.40-7.28 (m, 2H), 4.49-4.23 (m,4H), 3.70 (s, 3H), 2.69 (s, 3H), 2.16 (s, 3H) 754

MS (ESI) m/z 622.96 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 16.04 (s, 1H),8.18 (s, 1H), 8.02 (s, 1H), 8.01 (s, 1H), 7.71 (d, J = 8.36 Hz, 1H),7.65 (dd, J = 8.36,1.88 Hz, 1H), 7.58 (d, J = 1.72 Hz, 1H), 4.90 (s, 2H)3.64 (s, 3H), 2.73 (s, 3H), 2.36 (s, 3H) 774

MS (ESI) m/z 703.98 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H),8.32 (s, 1H), 8.05 (s, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.60 (dd, J =2.56, 8.88 Hz, 1H), 7.54 (d, J = 8.04 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J= 2.60 Hz, 1H), 7.36 (d, J = 8.96 Hz, 1H) 4.42 (t, J = 4.64 Hz, 2H),4.27 (t, J = 4.20 Hz, 2H), 2.90 (q, J = 7.52 Hz, 2H), 2.73 (s, 3H), 1.87(s, 3H), 1.32 ( t, J = 7.60 Hz, 3H) 775

MS (ESI) m/z 690.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H),8.52 (s, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.86 (s, 1H), 7.59 (dd, J =8.84, 2.52 Hz, 1H), 7.45 (s, 1H), 7.41 (d, J = 2.56 Hz, 1H), 7.36 (d, J= 8.96 Hz, 1H), 4.42 (t, J = 5.76 Hz, 2H), 4.28 (t, J = 4.24 Hz, 2H),2.73 (s, 3H), 2.43 (s, 3H), 1.87 (s, 3H) 776

MS (ESI) m/z 704.04 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H),8.06 (s, 1H), 7.92 (t, J = 7.80 Hz, 1H), 7.59 (dd, J = 8.80, 2.40 Hz,1H), 7.50-7.39 (m, 4H), 7.36 (d, J = 8.88 Hz, 1H), 4.40 (s, 2H), 4.27(s, 2H), 2.80 (q, J = 7.44 Hz, 2H), 2.72 (s, 3H), 1.84 (s, 3H), 1.22 (q,J = 7.44 Hz, 3H) 777

MS (ESI) m/z 693.96 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (dd, J =5.88, 7.96 Hz, 1H), 8.79 (d, J = 10.04 Hz, 1H), 8.34 (s, 1H), 8.12 (s,1H), 7.65-7.58 (m, 2H), 7.45 (s, 1H), 7.43 (d, J = 2.56 Hz, 1H), 7.37(d, J = 8.96 Hz, 1H), 4.45-4.26 (m, 4H), 2.72 (s, 3H), 1.87 (s, 3H) 779

MS (ESI) m/z 679.00 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H),8.02 (s, 1H), 7.87 (d, J = 1.92 Hz, 1H), 7.59 (dd, J = 8.88, 2.62 Hz,1H), 7.42 (d, J = 3.0 Hz, 2H), 7.35 (d, J = 8.96 Hz, 1H), 6.48 (s, 1H),4.40 (t, J = 6.04 Hz, 2H), 4.25 (t, J = 5.2 Hz, 2H), 3.93 (s, 3H), 2.70(s, 3H), 1.82 (s, 3H) 789

MS (ESI) m/z 670.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 with D20) δ 8.24(s, 1H), 7.97 (s, 1H), 7.56 (dd, J = 8.88, 2.52 Hz, 1H), 7.39-7.37 (m,2H), 7.31 (d, J = 8.96 Hz, 1H), 4.39-4.34 (m, 2H), 4.22 (bs, 2H), 3.05(s, 3H), 2.84 (s, 3H), 2.69 (s, 3H), 1.75 (s, 3H) 790

MS (ESI) m/z 622.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.95 (s, 1H), 7.59 (dd, J = 8.84, 2.52 Hz, 1H), 7.42 (s, 1H), 7.41 (d, J= 2.56 Hz, 1H), 7.35 (d, J = 8.96 Hz, 1H), 5.25 (s, 1H), 4.40 (t, J =4.52 Hz, 2H), 4.25 (t, J = 2.44 Hz, 2H), 2.70 (s, 3H), 1.79 (s, 3H) 808

MS (ESI) m/z 506.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H),7.34-7.24 (m, 2H), 6.98- 6.93 (m, 2H), 4.49 (t, J = 5.2 Hz, 2H), 4.31(t, J = 5.2 Hz, 2H), 3.85 (t, J = 12.3 Hz, 2H), 3.53 (d, J = 11.8 Hz,2H), 3.17 (d, J = 12.9 Hz, 2H), 3.05 (d, J = 11.6 Hz, 2H), 2.88 (s, 3H),2.77 (s, 3H) 832

MS (ESI) m/z = 584.1 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm =9.85-9.70 (b, 1H), 8.20 (s, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.40 (dd, J =8.9, 2.6 Hz, 1H), 7.17 (d, J = 8.9 Hz, 1H), 4.55 (t, J = 4.5 Hz, 2H),4.39 (t, J = 4.5 Hz, 2H), 3.84 (bt, J = 12.0 Hz, 2H), 3.53 (bd, J = 12.0Hz, 2H), 3.17 (d, J = 12.5 Hz, 2H), 3.12- 2.97 (m, 2H), 2.92-2.84 (m,6H) 833

MS (ESI) m/z = 582.1 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm =9.84-9.70 (b, 1H), 8.22 (s, 1H), 7.37 (dd, J = 8.8, 2.7, 1H), 7.34- 7.24(m, 5H), 7.23 (d, J = 2.7 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 4.41-4.30(m, 4H), 3.86 (bt, J = 12.6 Hz, 2H), 3.54 (bd, J = 11.5 Hz, 2H), 3.18(d, J = 12.5 Hz, 2H), 3.12-2.99 (m, 2H), 2.89 (bs, 3H), 2.23 (s, 3H) 834

MS (ESI) m/z = 683.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm =9.81-9.69 (b, 1H), 8.84 (d, J = 4.7 Hz, 1H), 8.23 (s, 1H), 7.96 (s, 1H),7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.48 (d, J = 4.7 Hz, 1H), 7.43 (d, J =2.7 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 4.41 (t, J = 5.1 Hz, 2H), 4.25(t, J = 5.1 Hz, 2H), 3.92-3.82 (m, 2H), 3.57 (bd, J = 11.2 Hz, 2H), 3.26(bd, J = 13.3 Hz, 2H), 3.15-3.02 (m, 2H), 2.92 (bs, 3H), 1.77 (s, 3H)835

MS (ESI) m/z = 611.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm =9.98-9.85 (b, 1H), 8.15 (s, 1H), 7.73-7.64 (bs, 2H), 7.55 (dd, J = 8.9,2.8 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H), 4.43(bs, 4H), 3.85 (bt, J = 11.1 Hz, 2H), 3.54 (bd, J = 11.4 Hz, 2H), 3.17(bd, J = 12.8 Hz, 2H), 3.12- 2.99 (m, 2H), 2.89 (s, 3H), 2.62 (s, 6H),2.37 (s, 3H) 836

MS (ESI) m/z = 653.0 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm =9.85-9.74 (b, 1H), 8.06 (s, 1H), 7.70 (d, J = 5.4 Hz, 1H), 7.55 (dd, J =8.9, 2.6 Hz, 1H), 7.36 (d, J = 2.6 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H),7.25 (d, J = 5.4 Hz, 1H), 7.18 (s, 1H), 4.38 (t, J = 4.7 Hz, 2H), 4.28(t, J = 4.7 Hz, 2H), 3.87 (bt, J = 13 Hz, 2H), 3.56 (bd, J = 11.7 Hz,2H), 3.25 (bd, J = 13 Hz, 2H), 3.15-3.01 (m, 2H), 2.91 (bs, 3H), 2.62(s, 3H), 1.96 (s, 3H) 847

LCMS: 694.4.5 [M + H]+; 1H NMR (400 MHz, DMSO- d6) δ 8.88 (d, J = 4.8Hz, 1H), 8.67 (d, J = 2.9 Hz, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.89 (dd,J = 9.0, 2.8 Hz, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.53 (d, J = 4.8Hz, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.43 (q, J= 4.9 Hz, 2H), 4.28 (q, J = 6.6, 5.9 Hz, 2H), 2.22 (s, 3H), 1.79 (s, 3H)852

LCMS: 669.6 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.59 (d,J = 4.7 Hz, 1H), 8.05 (s, 1H), 7.68 (d, J = 5.5 Hz, 1H), 7.52 (dd, J =8.9, 2.7 Hz, 1H), 7.38-7.26 (m, 3H), 7.18 (d, J = 4.7 Hz, 1H), 4.35 (t,J = 5.2 Hz, 2H), 4.24 (t, J = 4.9 Hz, 2H), 3.92 (d, J = 12.8 Hz, 2H),3.76 (t, J = 5.2 Hz, 2H), 3.60 (d, J = 12.0 Hz, 2H), 3.23 (dd, J = 26.4,8.6 Hz, 4H), 3.09 (s, 3H), 1.86 (s, 3H) 853

LCMS: 669.6 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 4.7 Hz,1H), 8.08 (s, 1H), 7.70 (d, J = 5.5 Hz, 1H), 7.52 (dd, J = 8.9, 2.7 Hz,1H), 7.42-7.34 (m, 2H), 7.29 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 4.7 Hz,1H), 4.43 (t, J = 5.4 Hz, 2H), 4.35 (t, J = 5.0 Hz, 2H), 4.23 (t, J =5.0 Hz, 2H), 3.14 (s, 5H), 3.01 (s, 2H), 2.83 (s, 5H), 1.83 (s, 3H) 855

MS (ESI) m/z 625.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =27.2 Hz, 2H), 8.62 (d, J = 4.7 Hz, 1H), 8.08 (s, 1H), 7.72 (d, J = 5.5Hz, 1H), 7.55 (dd, J = 8.9, 2.7 Hz, 1H), 7.44-7.26 (m, 3H), 7.21 (d, J =4.7 Hz, 1H), 4.38 (t, J = 5.0 Hz, 2H), 4.27 (t, J = 5.0 Hz, 2H), 3.38(s, 2H), 3.23 (s, 1H), 3.04 (s, 2H), 1.89 (s, 3H) 856

LCMS: 720.9 [M + H]+; 1H NMR (400 MHz, DMSO- d6) δ 9.81 (d, J = 9.6 Hz,1H), 8.59 (s, 1H), 8.09 (s, 1H), 7.79-7.63 (m, 3H), 7.50 (s, 1H), 4.85(s, 2H), 4.07-3.92 (m, 2H), 3.87-3.74 (m, 2H), 3.66 (d, J = 11.7 Hz,2H), 3.29 (d, J = 18.2 Hz, 4H), 3.14 (d, J = 11.5 Hz, 2H), 2.67 (s, 3H),2.23 (s, 3H) 859

LCMS: 707.4 [M + H; ]+. 1H NMR (400 MHz, DMSO- d6) δ 9.79 (s, 1H), 8.77(d, J = 4.8 Hz, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.76 (d, J = 8.3 Hz,1H), 7.72- 7.66 (m, 2H), 7.57 (d, J = 4.8 Hz, 1H), 4.87 (s, 2H), 3.98(d, J = 12.8 Hz, 2H), 3.80 (t, J = 5.2 Hz, 2H), 3.72-3.53 (m, 2H),3.39-3.21 (m, 4H), 3.21- 3.03 (m, 1H), 2.16 (s, 3H) 867

MS (ESI) m/z 732.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H),7.91 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J =2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 4.9 Hz, 2H), 4.24(t, J = 5.0 Hz, 2H), 3.98 (t, J = 11.9 Hz, 2H), 3.50 (d, J = 13.5 Hz,2H), 3.34 (d, J = 13.5 Hz, 2H), 3.18 (d, J = 12.0 Hz, 2H), 2.72 (s, 3H),1.81 (s, 3H) 870

MS (ESI) m/z 650.8 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.71-8.64 (m,2H), 8.29 (d, J = 0.6 Hz, 1H), 7.90 (dd, J = 9.2, 3.0 Hz, 1H), 7.78 (d,J = 5.6 Hz, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.48 (d, J = 5.5 Hz,1H), 7.41 (d, J = 2.7 Hz, 1H), 7.33 (d, J = 8.9 Hz, 1H), 7.26 (d, J =4.7 Hz, 1H), 4.43-4.35 (m, 2H), 4.34- 4.15 (m, 1H), 2.19 (d, J = 1.0 Hz,3H), 1.88 (s, 3H) 876

LCMS (ESI) m/z 678.8 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H),7.96 (s, 1H), 7.57 (dd, J = 8.9, 2.7 Hz, 1H), 7.43-7.36 (m, 2H), 7.33(d, J = 9.0 Hz, 1H), 4.38 (t, J = 4.9 Hz, 2H), 4.23 (t, J = 4.9 Hz, 2H),2.68 (s, 3H), 1.76 (s, 3H) 879

LCMS (ESI) m/z 697.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H),8.81 (s, 1H), 7.93 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.49-7.34(m, 3H), 4.41 (s, 2H), 4.26 (s, 2H), 3.79 (s, 7H), 3.40 (d, J = 12.1 Hz,2H), 3.18 (d, J = 12.2 Hz, 2H), 3.05 (s, 2H), 2.72 (s, 3H), 2.42 (s,3H), 1.97 (s, 3H) 887

LCMS (ESI) m/z 682.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =11.8 Hz, 1H), 8.76 (d, J = 4.9 Hz, 1H), 8.41 (d, J = 11.5 Hz, 1H), 7.94(s, 1H), 7.58 (dd, J = 8.9, 2.7 Hz, 1H), 7.49 (d, J = 4.9 Hz, 1H), 7.39(d, J = 2.7 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.1 Hz, 2H),4.22 (t, J = 5.0 Hz, 2H), 3.66 (s, 2H), 3.58 (s, 1H), 3.45 (d, J = 12.3Hz, 2H), 3.35 (s, 1H), 3.15-3.08 (m, 1H), 3.05 (d, J = 12.2 Hz, 1H),2.75 (d, J = 13.4 Hz, 2H), 2.30 (s, 3H), 1.85 (d, J = 17.3 Hz, 1H), 1.84(s, 3H 899

MS (ESI) m/z 643.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H),7.90 (s, 1H), 7.57 (dd, J = 8.80, 2.56 Hz, 1H), 7.31-7.30 (m, 2H), 4.41(t, J = 4.80 Hz, 2H), 4.33 (t, J = 4.80 Hz, 2H), 3.69 (s, 3H), 2.64 (s,3H), 2.31 (s, 3H), 2.27 (s, 3H) 901

MS (ESI) m/z 690.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H),8.65 (d, J = 4.60 Hz, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.60 (d, J =8.88, 2.44 Hz, 1H), 7.48 (bs, 1H), 7.46 (s, 1H), 7.44 (d, J = 2.48 Hz,1H), 7.36 (d, J = 8.96 Hz, 1H) 4.42 (t, J = 6.20 Hz, 2H), 4.32-4.22 (m,2H), 2.73 (s, 3H), 2.07 (s, 3H), 1.84 (s, 3H) 902

MS (ESI) m/z 704.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.41 (bs,1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.63-7.57 (m, 2H),7.46-7.40 (m, 2H), 7.36 (d, J = 8.80 Hz, 1H), 4.45-4.35 (m, 2H),4.35-4.23 (m, 2H), 2.72 (s, 3H), 2.35 (s, 3H), 2.15 (s, 3H), 1.83 (s,3H) 903

MS (ESI) m/z 704.16 [M +1]+; 1H NMR (400 MHz, DMSO-d6) 8.46 (s, 1H),8.30 (s, 1H), 8.24 (s, 1H), 7.84 (bs, 1H), 7.58-7.49 (m, 1H), 7.37 (s,1H), 7.29 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 4.37 (t, J = 4.68 Hz, 2H),4.27 (t, J = 4.2 Hz, 2H), 2.64 (s, 3H), 2.31 (s, 3H), 1.95 (s, 3H), 1.85(s, 3H) 904

MS (ESI) m/z 704.22 [M + 1]+;; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H),8.04 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.57 (dd, J = 8.88 Hz, 2.4 Hz,1H), 7.43 (s, 2H), 7.40-7.34 (m, 2H), 4.40 (t, J = 4.48 Hz, 2H), 4.22(t, J = 5.2 Hz, 2H), 2.72 (s, 3H), 2.50 (s, 3H), 2.36 (s, 3H), 1.82 (s,3H) 905

MS (ESI) m/z 704.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H),8.04 (s, 1H), 7.59 (dd, J = 8.84 Hz, 2.60 Hz, 1H), 7.43 (s, 2H), 7.36(d, J = 8.96 Hz, 1H), 7.30 (s, 1H), 7.25 (s, 1H), 4.40 (s, 2H), 4.27 (s,2H), 2.72 (s, 3H), 2.50 (s, 3H), 2.39 (s, 3H), 1.82 (s, 3H) 906

MS (ESI) m/z 704.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.52 (bs,1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.72 (d, J = 7.88 Hz, 1H), 7.59 (dd, J= 8.88, 2.4 Hz, 1H), 7.45-7.43 (m, 2H), 7.36-7.31 (m, 2H), 4.43 (t, J =4.36 Hz, 2H), 4.26 (t, J = 5.88 Hz, 2H), 2.72 (s, 3H), 2.46 (s, 3H),2.04 (s, 3H), 1.80 (s, 3H) MS (ESI) m/z 679.00 [M + 1]+; 1H NMR (400MHz, 907

DMSO-d6) δ 13.56 (bs, 1H), 8.40 (s, 1H), 7.99 (s, 1H), 7.77 (s, 1H),7.58 (d, J = 7.20 Hz, 1H), 7.42-7.34 (m, 4H), 4.39 (s, 2H), 4.25 (s,2H), 3.77 (s, 3H), 2.69 (s, 3H), 1.82 (s, 3H) 908

MS (ESI) m/z 670.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H)9.15 (d, J = 5.08 Hz, 1H), 8.64 (s, 1H), 8.27 (s, 1H), 7.97 (d, J = 5Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.70-7.67 (m, 1H), 7.65 (d, J = 0.84Hz, 1H), 7.49 (s, 1H), 4.89 (s, 2H), 2.64 (s, 3H), 2.22 (s, 3H) 909

MS (ESI) m/z 684.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (bs,1H), 8.23 (s, 1H), 7.93 (s, 1H), 7.59 (dd, J = 2.44, 8.84 Hz, 1H), 7.41(d, J = 2.76 Hz, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.40 (t, J = 4.20 Hz,2H), 4.25 (t, J = 5.88 Hz, 2H), 4.16 (s, 2H), 3.17 (s, 3H), 2.86 (s,3H), 2.69 (s, 3H), 1.82 (s, 3H) 934

MS (ESI) m/z 722.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.5 (bs,1H),8.24 (s, 1H), 8.05 (s, 1H), 7.59 (dd, J = 8.88, 2.4 Hz, 1H), 7.43-7.40(m, 4H), 7.36 (d, J = 9.2 Hz,1H), 5.55 (d, J = 44 Hz, 2H), 4.41 (t, J =5.2 Hz, 2H), 4.27 (t, J = 5.2 Hz, 2H), 2.72 (s, 3H), 2.58 (s, 3H), 1.84(s, 3H) 937

MS (ESI) m/z 688.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),8.06 (s, 1H), 7.41-7.35 (m, 2H), 7.25 (dd, J = 8.56, 2.84 Hz, 1H), 4.38(t, J = 4.48 Hz, 2H), 4.27 (t, J = 4.32 Hz, 2H), 2.72 (s, 3H), 2.63 (s,6H), 1.90 (s, 3H) 963

MS (ESI) m/z 705.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.54 (bs,1H), 8.33 (s, 1H), 8.07 (s, 1H), 7.60 (dd, J = 2.48, 8.90 Hz, 1H), 7.55(s, 1H), 7.43-7.42 (m, 2H), 7.36 (d, J = 8.92 Hz, 1H), 4.41 (bs, 2H),4.27 (bs, 2H), 2.72 (s, 3H), 2.65 (s, 1H), 2.56 (s, 1H), 1.84 (s, 3H)964

MS (ESI) m/z 709.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (bs,1H), 9.14 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 7.60 (dd, J = 2.56, 8.92Hz, 1H), 7.44-7.43 (m, 2H), 7.36 (d, J = 8.96 Hz, 1H), 4.42 (t, J = 5.20Hz, 2H), 4.27 (t, J = 4.52 Hz, 2H), 2.73 (s, 3H), 2.70 (s, 3H), 1.82 (s,3H) 965

MS (ESI) m/z 705.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H),8.11 (s, 1H), 7.58 (d, J = 8.84 Hz, 1H), 7.46-7.39 (m, 3H), 7.34 (d, J =8.88 Hz, 1H), 4.39 (t, J = 4.76 Hz, 2H), 4.26 (t, J = 4.44, Hz, 2H),2.70 (s, 3H), 2.49 (s, merged, 6H), 1.77 (s, 3H) 966

MS (ESI) m/z 695.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.43 (s, 1H)9.22 (s, 2H), 8.35 (s, 1H), 8.17 (s, 1H), 7.57 (t, J = 6.56 Hz, 1H),7.42 (d, J = 2.24 Hz, 1H), 7.38 (s, 1H), 7.34 (d, J = 8.88 Hz, 1H), 4.39(t, J = 2.96 Hz, 2H), 4.27 (t, J = 3.88 Hz, 2H), 2.69 (s, 3H), 1.82 (s,3H) 967

MS (ESI) m/z 691.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.29 (bs, 1H),8.16 (bs, 1H), 7.94 (bs, 1H), 7.86-7.83 (m, 1H), 7.59 (d, J = 7.16 Hz,1H), 7.41-7.28 (m, 3H), 4.41 (bs, 2H), 4.30 (bs, 2H), 2.76 (s, 3H), 2.50(bs, 3H), 1.86 (bs, 3H) 968

MS (ESI) m/z 705.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 ) 8.63 (s, 1H),8.37 (s, 1H), 8.14 (s, 1H), 7.60 (dd, J = 8.88, 2.52 Hz, 1H), 7.48-7.43(m, 2H), 7.36 (d, J = 8.96 Hz, 1H), 4.48-4.35 (m, 2H), 4.30- 4.24 (m,2H), 2.73 (m, 3H), 2.52 (m, 3H), 2.29 (m, 3H), 1.80 (s, 3H) 969

MS (ESI) m/z 705.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H),8.36 (s, 1H), 8.08 (s, 1H), 7.60 (dd, J = 8.80, 2.48 Hz,1H), 7.45-7.42(m, 2H), 7.36 (d, J = 8.92, 1H), 4.44-4.38 (m, 2H), 4.31-4.23 (m, 2H),2.72 (s, 3H), 2.66 (s, 3H), 2.57 (s, 3H), 1.84 (s, 3H) 991

MS (ESI) m/z 714.06 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H),7.90 (s, 1H), 7.59 (dd, J = 8.84, 2.40 Hz, 1H), 7.46-7.40 (m, 2H), 7.36(d, J = 9.00, 1H), 4.39 (t, J = 4.48 Hz, 2H), 4.23 (t, J = 4.08 Hz, 3H),3.60-3.40 (m, 2H), 3.20-3.02 (m, 2H), 3.01- 2.80 (m, 1H), 2.70 (s, 3H),2.30-2.10 (m, 2H), 2.00- 2.82 (m, 2H), 1.81 (s, 3H) 992

MS (ESI) m/z 700.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 8.26 (s, 1H),7.89 (s, 1H), 7.63-7.58 (m, 1H), 7.44-7.39 (m, 2H), 7.36 (d, J = 8.8 Hz,1H), 4.39 (s, 2H), 4.23 (s, 2H), 3.71-3.50 (m, merged, 2H), 3.31-3.20(m, 2H), 2.87-.73 (m, 2H), 2.71 (s, 3H), 2.69-2.60 (m. 2H), 1.80 (s, 3H)995

MS (ESI) m/z 744.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.20 (bs,1H), 8.35 (s, 1H), 8.29-8.25 (m, 1H), 8.22 (s, 1H), 8.09-8.06 (m, 1H),7.57 (d, J = 9.24 Hz, 1H), 7.43-7.33 (m, 3H), 7.07 (t, J = 54.36 Hz,1H), 4.39 (bs, 2H), 4.27 (bs, 2H), 2.69 (s, 3H), 1.83 (s, 3H) 996

MS (ESI) m/z 642.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H),7.89 (s, 1H), 7.59 (dd, J = 2.60, 8.88 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J= 2.64 Hz, 1H), 7.36 (d, J = 8.96 Hz, 1H), 4.39 (t, J = 4.68 Hz, 2H),4.23 (t, J = 4.64 Hz, 2H), 2.94 (s, 6H), 2.70 (s, 3H), 1.81 (s, 3H) 1009

MS (ESI) m/z 684.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H),8.39 (s, 1H), 7.77 (s, 1H), 7.58 (dd, J = 2.44, 8.84 Hz, 1H), 7.41-7.39(m, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.65-4.62 (m, 2H), 4.37 (bs, 2H),4.32-4.27 (m, 3H), 4.18 (bs, 2H), 3.37 (s, 3H), 2.70 (s, 3H), 1.74 (s,3H) 1012

MS (ESI) m/z 690.14 [M + 1]+; ; 1H NMR (400 MHz, DMSO-d6): δ 13.74 (s,1H), 8.71 (d, J = 5.0 Hz, 2H), 8.26 (s,1H), 8.041 (s, 1H), 7.61 (dd, J =7.2.24 Hz, J = 2.20 Hz,1H), 7.54 (d, J = 4.64 Hz, 2H), 7.48 (s, 1H),7.44 (d, J = 2.24 Hz, 1H), 7.38 (d, J = 8.88 Hz, 1H), 4.43 (t, J = 4.52Hz, 2H), 4.27 (t, J = 4.44 Hz, 2H), 3.06 (m, 2H), 1.80 (s, 3H), 1.39 (t,J = 7.52 Hz, 3H) 1013

MS (ESI) m/z 690.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.12 Hz, 1H), 8.69 (s, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.98 (d, J =7.68 Hz, 1H), 7.65-7.59 (m, 2H), 7.49 (s, 1H), 7.44 (d, J = 2.48 Hz,1H), 7.38 (d, J = 8.96 Hz, 1H), 4.43 (t, J = 4.52 Hz, 2H), 4.27 (t, J =4.44 Hz, 2H), 3.06 (m, 2H), 1.80 (s, 3H), 1.39 (t, J = 7.52 Hz, 3H) 1014

MS (ESI) m/z 693.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H),8.00 (s, 1H), 7.87 (d, J = 2.56 Hz, 1H), 7.60 (dd, J = 2.56, 8.88 Hz,1H), 7.46 (s, 1H), 7.44 (d, J = 2.44 Hz, 1H), 7.35 (d, J = 9.00 Hz, 1H),6.48 (s, 1H), 4.40 (t, J = 4.56 Hz, 2H), 4.24 (t, J = 4.72 Hz, 2H), 3.93(s, 3H), 3.02 (q, J = 7.36, 2H), 1.76 (s, 3H), 1.35 (t, J = 7.52 Hz, 3H)1017

MS (ESI) m/z 722.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.72 (bs,1H), 8.67 (d, J = 2.68 Hz, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.90 (d, J =6.68 Hz, 1H), 7.59 (dd, J = 2.48, 8.92 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J= 2.48 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 3.88 Hz, 2H),4.28 (bs, 2H), 3.04 (q, J = 7.2 Hz, 2H), 2.21 (s, 3H), 1.79 (s, 3H),1.39 (t, J = 7.2 Hz, 3H) 1025

MS (ESI) m/z 727.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.54 (bs,1H), 9.24 (s, 1H), 9.22 (s, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.60 (dd, J= 2.52, 8.84 Hz, 1H), 7.43-7.17 (m, 4H), 4.42 (bs, 2H), 4.28 (bs, 2H),2.72 (s, 3H), 1.87 (s, 3H) 1026

MS (ESI) m/z 745.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H),9.49 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.61 (dd, J = 2.48, 8.8 Hz,1H), 7.44- 7.42 (m, 2H), 7.37 (d, J = 8.8 Hz, 1H), 4.42 (bs, 2H), 4.30(bs, 2H), 2.72 (s, 3H), 1.89 (s, 3H) 1027

MS (ESI) m/z 693.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H),8.04 (s, 1H), 7.65 (s, 1H), 7.59 (dd, J = 8.92 Hz, 1.48 Hz, 1H), 7.44(s, 2H), 7.36 (s, 1H),4.41 (s, 2H), 4.25 (s, 2H), 3.86 (s, 3H), 2.71 (s,3H), 1.86 (s, 3H), 1.79 (s, 3H) 1028

MS (ESI) m/z 693.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H),8.32 (s, 1H), 8.07 (s, 1H), 7.61 (dd, J = 2.56 Hz, J = 8.88 Hz, 1H),7.45- 7.43 (m, 2H), 7.37 (d, J = 9.00 Hz, 1H), 6.27 (s, 1H), 4.41 (bs,3H), 4.27 (bs, 2H), 3.55 (s, 3H), 2.72 (s, 3H), 2.23 (s, 3H), 1.84 (s,3H) 1029

MS (ESI) m/z 693.00 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (bs,1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.59 (dd, J = 8.88, 2.4 Hz, 1H),7.43-7.41 (m, 3H), 7.35 (d, J = 8.8 Hz, 1H), 4.40 (t, J = 6.04 Hz, 2H),4.25 (t, J = 5.2 Hz, 2H), 3.83 (s, 3H), 2.70 (s, 3H), 2.10 (s, 3H), 1.83(s, 3H) 1030

MS (ESI) m/z 693.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (bs,1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.61 (dd, J1 = 6.48, J2 = 2.28 Hz 1H),7.45-7.43 (m, 3H), 7.38 (d, J = 8.88 Hz, 1H), 4.42 (bs, 2H), 4.26 (bs,2H), 3.57 (s, 3H), 2.72 (s, 3H), 1.82 (s, 6H) 1031

MS (ESI) m/z 693.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.56 (bs,1H), 8.34 (s, 1H), 8.00 (s, 1H), 7.77 (s, 1H), 7.59 (dd, J = 8.84, 2.40Hz, 1H), 7.43 (s, 2H), 7.36 (d, J = 8.96 Hz, 1H), 4.48-4.36 (m, 2H),4.35-4.19 (m, 2H), 3.86 (s, 3H), 2.70 (s, 3H), 1.97 (s, 3H), 1.84 (s,3H) 1032

MS (ESI) m/z 693.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H),8.01 (s, 1H), 7.60 (dd, J = 9.92, 3.32 Hz, 1H), 7.45-7.39 (m, 3H), 7.36(d, J = 8.88 Hz, 1H), 4.46-4.45 (m, 2H), 4.30-4.20 (m, 2H), 3.83 (s,3H), 2.70 (s, 3H), 2.10 (s, 3H), 1.83 (s, 3H) 1033

MS (ESI) m/z 706.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J =4.4 Hz, 1H), 8.28 (s, 1H), 8.00-7.95 (m, 2H), 7.72 (d, J = 7.72 Hz, 1H),7.60 (dd, J = 8.88, 2.56 Hz, 1H), 7.46-7.39 (m, 3H), 7.37 (d, J = 8.96Hz, 1H), 5.45 (s, 2H), 4.42 (t, J = 3.8 Hz, 2H), 4.25 (t, J = 4.3 Hz,2H), 2.72 (s, 3H), 1.80 (s, 3H) 1034

MS (ESI) m/z 655.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.54 (bs,1H), 8.29 (s, 1H), 7.90 (s, 1H), 7.59 (dd, J = 8.92, 2.32 Hz, 1H), 7.42(s, 2H), 7.36 (d, J = 8.92 Hz, 1H), 4.77-4.70 (m, 1H), 4.40 (t, J = 6.64Hz, 2H), 4.23 (t, J = 5.12 Hz, 2H), 2.70 (s, 3H), 1.76 (s, 3H),0.92-0.75 (m, 4H) 1035

MS (ESI) m/z 792.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.45 (bs,1H), 8.44 (d, J = 2.52 Hz, 1H), 8.38 (d, J = 3.32 Hz, 1H), 8.34 (s, 1H),8.11 (s, 1H), 7.60 (dd, J = 2.55, 8.88 Hz, 1H), 7.49-7.42 (m, 4H), 7.35(d, J = 8.90 Hz, 1H), 4.41 (t, J = 5.24 Hz, 2H), 4.05 (t, J = 4.0 Hz,2H), 2.72 (s, 3H), 1.77 (s, 3H) 1036

MS (ESI) m/z 629.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H),7.91 (s, 1H), 7.60 (dd, J = 8.92, 2.56 Hz, 1H), 7.43 (s, 1H)- 7.42, (d,J = 2.80 Hz, 1H), 7.36 (d, J = 8.96 Hz, 1H), 4.40 (t, J = 4.72 Hz, 2H),4.24 (t, J = 4.48 Hz, 2H), 4.13 (s, 3H), 2.71 (s, 3H), 1.78 (s, 3H) 1046

MS (ESI) m/z 639.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H),7.90 (s, 1H), 7.59 (dd, J = 8.84, 2.40 Hz, 1H), 7.44-7.39 (m, 2H), 7.35(d, J = 8.92 Hz, 1H), 4.38 (t, J = 5.56 Hz, 2H), 4.24 (t, J = 6.04 Hz,2H), 2.69 (s, 3H), 2.30-2.18 (m, 1H) 1.83 (s, 3H), 1.26-1.12 (m, 2 h),1.00-0.90 (m, 2H) 1049

MS (ESI) m/z 639.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H),7.90 (s, 1H), 7.59 (dd, J = 8.84, 2.40 Hz, 1H), 7.44-7.39 (m, 2H), 7.35(d, J = 8.92 Hz, 1H), 4.38 (t, J = 5.56 Hz, 2H), 4.24 (t, J = 6.04 Hz,2H), 2.69 (s, 3H), 2.30-2.18 (m, 1H) 1.83 (s, 3H), 1.26-1.12 (m, 2 h),1.00-0.90 (m, 2H) 1055

MS (ESI) m/z 684.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H),8.40 (s, 1H), 7.77 (s, 1H), 7.59 (dd, J = 2.28 Hz, J = 8.84 Hz, 1H),7.42 (d, J = 2.40 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J = 8.88, 1H), 5.72(s, 1H), 4.39-4.30 (m, 6H), 4.18 (t, J = 6.68, 2H), 2.70 (s, 3H), 1.73(s, 3H), 1.45 (s, 3H) 1058

MS (ESI) m/z 706.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.49 (bs,1H), 8.27 (s, 1H), 8.05 (s, 1H), 7.56-7.48 (m, 2H), 7.39 (s, 1H), 4.41(t, J = 5.52 Hz, 2H), 4.27 (t, J = 5.04 Hz), 2.72 (s, 3H), 2.61 (s, 6H),1.86 (s, 3H) 1059

MS (ESI) m/z 710.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 8.57 (d, J = 1.6Hz, 1H), 8.27 (s, 1H), 8.10-8.03 (m, 2H), 7.79 (d, J = 8.2 Hz,1H), 7.60(dd, J = 8.8, 2.6 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.36(d, J = 8.9 Hz, 1H), 4.42 (t, J = 4.24 Hz, 2H), 4.28 (t, J = 5.4 Hz,2H), 2.73 (s, 3H), 1.87 (s, 3H) 1030

MS (ESI) m/z 667.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.53 (bs,1H), 8.35 (d, J = 2.68 Hz, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.60 (dd, J= 8.84, 2.36 Hz, 1H), 7.46-7.40 (m, 3H), 7.36 (d, J = 8.96 Hz, 1H),4.50-4.20 (m, 4H), 3.86 (s, 3H), 2.72 (s, 3H), 2.12 (s, 3H), 1.86 (s,3H) 1073

MS (ESI) m/z 643.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H),7.91 (s, 1H), 7.59 (dd, J = 8.84 Hz, 2.56 Hz, 1H), 7.43-7.41 (m, 2H),7.36 (d, J = 8.96 Hz, 1H), 4.40-4.35 (m, 4H), 4.23 (t, J = 4.16 Hz, 2H),2.70 (s, 3H), 1.78 (s, 3H), 1.46 (t, J = 6.96 Hz, 3H) 1074

MS (ESI) m/z 697.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 ) 8.21 (s, 1H),7.96 (s, 1H), 7.59 (d, J = 8.96 Hz, 1H), 7.43 (s, 1H), 7.41 (s, 1H),7.36 (d, J = 8.96 Hz, 1H), 5.00 (q, J = 8.40 Hz, 2H), 4.41 (t, J = 5.24Hz, 2H), 4.25 (t, J = 4.8 Hz, 2H), 2.72 (s, 3H), 1.79 (s, 3H) 1075

MS (ESI) m/z 711.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H),8.06 (s, 1H), 7.59 (d, J = 8.84 Hz, 1H), 7.43 (d, J = 5.5 Hz, 2H), 7.36(d, J = 8.9 Hz, 1H), 4.46-3.64 (m, 10H), 2.82 (s, 3H), 2.71 (s, 3H),1.85 (s, 3H) 1079

MS (ESI) m/z 767.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 with D20) δ 8.00(d, J = 6.4 Hz, 2H), 7.53 (d, J = 7.2 Hz, 1H), 7.33 (s, 1H), 7.27 (d, J= 8.4 Hz, 1H), 7.19 (s, 1H), 4.33 (bs, 2H), 4.20 (bs, 2H), 2.54 (s, 3H),2.19 (s, 3H), 1.67 (s, 3H) 1080

MS (ESI) m/z 751.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H),7.94 (s, 1H), 7.53 (dd, J = 8.76, 2.16 Hz, 1H), 7.40 (d, J = 2.16 Hz,1H), 7.29 (d, J = 8.92 Hz, 1H), 7.19 (s, 1H), 7.00 (d, J = 6.52, Hz,1H), 5.76-5.68 (m, 1H), 4.40-4.30 (m, 2H), 4.30-4.15 (m, 2H), 3.70-3.45(m, 2H), 3.10-2.70 (m, 2H), 2.60 (s, 3H), 2.35-1.90 (m, 7H), 1.69 (s,3H) 1081

MS (ESI) m/z 805.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J =2.76 Hz, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.97 (d, J = 6.76 Hz, 1H),7.57 (dd, J = 2.56, 8.8 Hz, 1H), 7.36 (t, J = 2.56 Hz, 2H), 7.28 (s,1H), 4.41-4.21 (m, 6H), 2.82 (bs, 2H), 2.64 (s, 3H), 2.50 (s, 4H), 2.19(s, 3H), 1.91 (s, 3H), 1.69 (s, 4H) 1082

MS (ESI) m/z, 867.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H),7.96 (s, 1H), 7.57 (dd, J = 2.52, 8.88 Hz, 1H), 7.36 (d, J = 2.52 Hz,1H), 7.32 (d, J = 9.0 Hz, 1H), 7.27 (s, 1H), 6.94-6.90 (m, 1H),4.61-4.56 (m, 1H), 4.37 (bs, 2H), 4.23 (bs, 2H), 3.60 (bs, 2H), 2.95(bs, 2H), 2.63 (s, 3H), 2.24 (s, 4H), 1.84 (bs, 2H), 1.75 (s, 3H), 1.63(d, J = 5.36 Hz, 6H), 1.44-1.39 (m, 4H), 1.33-1.20 (m, 4H) 1085

MS (ESI) m/z 711.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H),7.91 (s, 1H), 7.61 (dd, J = 8.9 Hz, 2.44 Hz, 1H), 7.47 (s, 1H), 7.43 (d,J = 2.4 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H),4.24 (t, J = 4.0 Hz, 2H), 3.86 (t, J = 9.2 Hz, 2H), 3.55 (bs, 2H), 3.32(bs, 2H), 3.10 (bs, 2H), 3.02 (q, J = 15.0 Hz, 2H), 2.89 (s, 3H), 1.79(s, 3H), 1.36 (t, J = 7.5 Hz, 3H) 1087

MS (ESI) m/z 725.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.50 (bs,1H), 7.92 (s, 1H), 7.60 (dd, J = 2.52, 9.28 Hz, 1H), 7.47 (s, 1H), 7.43(d, J = 2.28 Hz, 1H), 7.36 (d, J = 8.88 Hz, 2H), 4.40 (t, J = 5.56 Hz,2H), 4.24 (t, J = 5.76 Hz, 2H), 3.86 (t, J = 11.28 Hz, 2H), 3.56 (d, J =11.44 Hz, 2H), 3.21-3.18 (m, 2H), 3.08 (d, J = 10.4 Hz, 2H), 3.01 (q, J= 7.6 Hz, 2H), 2.90 (bs, 3H), 2.37 (s, 3H), 1.90 (s, 3H), 1.36 (t, J =7.6 Hz, 3H) 1088

MS (ESI) m/z 708.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H),10.02 (bs,1H), 8.21 (d, J = 5.4 Hz, 1H), 7.97 (d, J = 5.48 Hz, 1H), 7.62(d, J = 2.28 Hz, 1H), 7.47 (s, 1H), 7.43 (d, J = 2.24 Hz, 1H), 7.37 (d,J = 8.96 Hz, 1H), 5.95 (s, 1H), 4.42 (bs, 2H), 4.39 (bs, 2H), 4.26 (d, J= 4.55 Hz, 1H), 3.85- 3.65 (m, 2H), 3.4-3.33 (m, 1H), 3.04-2.99 (m, 6H),2.67 (bs, 1H), 1.86 (s, 3H), 1.36 (t, J = 7.52, 3H) 1093

MS (ESI) m/z 697.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =4.9 Hz, 1H), 7.95 (s, 1H), 7.61 (dd, J = 2.5, 8.8 Hz, 1H), 7.52 (d, J =4.8 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.42(t, J = 4.8 Hz, 2H), 4.26 (t, J = 4.3 Hz, 2H), 3.90-3.83 (m, 2H),3.57-3.54 (m, 2H), 3.21-3.18 (m, 2H), 3.10-3.08 (m, 2H), 2.91 (s, 3H),2.39 (s, 3H), 1.85 (s, 3H) 1151

MS (ESI) m/z 760.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.56 (bs,1H), 8.89 (d, J = 4.8 Hz, 1H), 8.36 (s, 1H), 7.97 (s, 1H), 7.60 (dd, J =8.8, 2.4 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.45 (d, J = 2.8 Hz, 1H),7.36 (d, J = 9.2 Hz, 1H), 4.45-4.38 (m, 2H), 4.26-4.19 (m, 2H),3.80-3.40 (m, 5H), 3.20-2.75 (m, 4H), 2.65- 2.50 (s, 2H), 2.27 (s, 3H),1.68 (s, 3H) 1153

MS (ESI) m/z 683.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 13.12 (bs, 1H),8.85 (d, J = 4.8 Hz, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.60 (d, J = 9.2,2.4 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36(d, J = 9.2 Hz, 1H), 5.00 (q, J = 8.4 Hz, 2H), 4.41 (s, 2H), 4.25 (s,2H), 1.73 (s, 3H) 1154

MS (ESI) m/z 620.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (bs,1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.67-7.62 (m, 3H), 7.51 (bs, 2H), 7.37(bs, 1H), 5.02 (s, 2H), 3.87-3.45 (m, 4H), 3.21-2.91 (m, 4H), 3.02 (bs,3H), 2.85 (bs, 3H) 1156

MS (ESI) m/z 765.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.26 (bs,1H), 8.82 (d, J = 4.8 Hz, 1H), 8.28 (s, 1H), 7.93 (s, 1H), 7.59 (d, J =8.8 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 10.8Hz, 1H), 4.39 (bs, 2H), 4.23 (bs, 2H), 3.63 (bs, 2H), 3.31 (bs, 2H),2.95 (m, 4H), 2.60 (t, J = 7.2 Hz, 4H), 1.71 (s, 3H) 1158

MS (ESI) m/z 721.16 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.41 (s, 1H), 7.83 (s, 1H), 7.60 (dd, J = 2.4, 8.4 Hz, 1H),7.44 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 4.71 (s, 2H), 4.63(s, 2H), 4.40-4.20 (m, 8H), 3.05 (bs, 1H), 1.73 (s, 3H), 0.79-0.77 (m,4H) 1159

MS (ESI) m/z 709.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.4 Hz, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.60 (dd, J = 6.4 Hz, 2.4 Hz,1H), 7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J =8.8 Hz, 1H), 4.40 (s, 2H), 4.24 (s, 2H), 3.85 (s, 4H), 3.29 (bs, 4H),3.12 (bs, 1H), 1.76 (s, 3H), 1.01 (s, 2H), 0.85 (s, 2H) 1178

MS (ESI) m/z 715.47 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =5.2 Hz, 1H), 8.66 (s, 1H), 7.93 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.70-7.66 (m, 2H), 7.56 (d, J = 4.4 Hz, 1H), 4.82 (s, 2H), 4.73-4.41 (m,8H), 3.05 (bs, 1H), 2.11 (s, 3H), 0.77 (bs, 4H) 1179

MS (ESI) m/z 786.04 [M + 1]+. 1H-NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H),8.94 (d, J = 4.8 Hz, 1H), 8.31 (s, 1H), 7.97 (s, 1H), 7.63- 7.58 (m,2H), 7.45 (d, J = 2.40 Hz, 1H), 7.37 (d, J = 9.20 Hz, 1H), 4.42 (bs,2H), 4.22 (bs, 2H), 3.86-3.66 (m, 4H), 3.57 (s, 3H), 3.28- 3.122 (m,5H), 1.67 (s, 3H), 2.01-0.84 (m, 4H) 1192

MS (ESI) m/z 717.23 [M + 1]+; 1H NMR (400 MHz, DMSO) δ 13.50 (bs, 1H),8.27 (s, 1H), 8.05 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 8.0,4.0 Hz, 1H), 7.43 (s, 2H), 7.36 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 6.42(d, J = 4.0 Hz, 1H), 4.41 (s, 2H), 4.26 (s, 2H), 3.46 (t, J = 8.0 Hz,2H), 2.83-2.60 (m, 5H), 1.84 (s, 3H) 1197

MS (ESI) m/z 679.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.46 (bs,1H), 8.23 (s, 1H), 7.94 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H),7.41 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.46 (t, J = 52.0Hz, 1H), 4.70-4.60 (m, 2H), 4.41 (s, 2H), 4.24 (s, 2H), 2.71 (s, 3H),1.79 (s, 3H) 1200

MS (ESI) m/z 684.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.29 (bs,1H), δ 10.03 (bs, 1H), δ 7.98 (s, 1H), δ 7.61 (dd, J = 9.0 Hz, 2.46 Hz,1H), 7.43 (s, 1H), 7.42 (s, 1H), 7.35 (d, J = 9.2 Hz, 1H), 4.41 (t, J =5.1 Hz, 2H), 4.28 (t, J = 4.5 Hz, 2H), 3.42 (bs, 2H), 3.32 (bs, 2H),2.93 (s, 6H), 2.70 (s, 3H), 2.34 (s, 3H), 1.96 (s, 3H) 1206

MS (ESI) m/z 723.34 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.6 Hz, 1H), 8.19 (s, 1H), 7.90 (s ,1H), 7.58 (dd, J = 2.48, 8.92 Hz,1H), 7.38 (d, J = 3.16 Hz, 1H), 7.33 (d, J = 8.96 Hz, 1H), 4.39 (t, J =5.4 Hz, 2H), 4.22 (t, J = 5.2 Hz, 2H), 3.89 (s, 3H), 3.80-3.40 (m, 4H),3.10-2.90 (m, 4H), 1.69 (s, 3H), 0.47- 0.35 (m, 4H) 1207

MS (ESI) m/z 779.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.32 (bs,1H), 7.90 (s, 1H), 7.60 (dd, J = 2.6, 8.9 Hz, 1H), 7.41 (m, 2H), 7.36(d, J = 8.9 Hz, 1H), 4.40 (s, 2H), 4.26 (s, 2H), 3.66 (m, 2H), 3.20 (m,2H), 2.97 (m, 2H), 2.70 (s, 3H), 2.66 (m, 1H), 2.49 (s, 3H), 2.44 (s,3H), 1.97 (s, 3H) 1212

MS (ESI) m/z 677.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.11 (bs,1H), 8.77 (d, J = 4.8 Hz, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.76 (d, J =8.4 Hz, 1H), 7.71-7.67 (m, 2H), 7.56 (d, J = 4.8 Hz, 1H), 4.86 (s, 2H),3.89-3.86 (m, 2H), 3.59-3.56 (m, 2H), 3.29 (d, J = 11.6 Hz, 2H), 3.11(bs, 2H), 2.92 (s, 3H), 2.17 (s, 3H) 1213

MS (ESI) m/z 691.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H),9.77 (s, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 7.76-7.64 (m, 3H), 7.50 (s,1H), 4.84 (s, 2H), 3.93-3.88 (m, 2H), 3.61-3.58 (m, 2H), 3.32-3.29 (m,2H), 3.12 (bs, 2H), 2.92 (s, 3H), 2.67 (s, 3H), 2.23 (s, 3H) 1214

MS (ESI) m/z 700.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.83 (bs,1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.52-7.50 (m, 1H), 7.29-7.20 (m, 4H),4.34 (bs, 2H), 4.22 (bs, 2H), 3.60-3.38 (m, 2H), 3.25 (bs, 2H),3.19-2.98 (m, 4H), 2.24 (s, 3H), 1.79 (s, 3H) 1215

MS (ESI) m/z 713.31 [M + 1]+;1H NMR (400 MHz, DMSO-d6) δ 13.66 (bs, 1H),9.74 (bs, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.60-7.54 (m, 2H), 7.44 (s,1H), 4.39 (bs, 2H), 4.23 (bs, 2 H), 3.86 (m, 2H), 3.58 (m, 2H),3.26-2.98 (m, 6H), 2.89 (s, 3H), 1.79 (s, 3H), 1.35 (t, J = 7.6 Hz, 3H)1218

MS (ESI) m/z 696.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H),8.02 (s, 1H), 7.66 (s, 1H), 7.50 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H),7.27-7.25 (m, 3H), 7.13 (d, J = 7.6 Hz, 1H), 4.34 (t, J = 4.8 Hz, 2H),4.22 (t, J = 4.8 Hz, 2H), 3.86 (t, J = 10.8, 2H), 3.55-3.53 (m, 2H),3.24-3.21 (m, 2H), 3.07 (bs, 2H), 2.89 (s, 3H), 2.68 (s, 3H), 1.7 (s,3H) 1221

MS (ESI) m/z 627.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.02 (bs,1H), 9.72 (bs, 1H), 8.58 (d, J = 4.4 Hz, 1H), 8.15 (s, 1H), 7.90 (s,1H), 7.54 (d, J = 4.2 Hz, 1H), 7.48 (dd, J = 8.8, 2.5 Hz, 1H), 7.40 (d,J = 2.4 Hz, 1H), 7.25 (d, J = 9.6 Hz, 1H), 4.39 (s, 4H), 3.85 (t, J =11.3 Hz, 2H), 3.52 (t, J = 11.2 Hz, 2H), 3.21 (d, J = 11.8 Hz, 2H), 3.07(bs, 2H), 2.89 (s, 3H), 2.24 (s, 3H) 1222

MS (ESI) m/z 641.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.73 (bs, 1H),8.10 (s, 1H), 7.70 (s, 1H), 7.50-7.40 (m, 2H), 7.35 (d, J = 2.8 Hz, 1H),7.25 (d, J = 9.2 Hz, 1H), 4.38 (s, 4H), 3.85 (t, J = 22.8 Hz, 2H), 3.54(d, J = 11.2 Hz, 2H), 3.21 (d, J = 11.6 Hz, 2H), 3.13-2.98 (m, 2H), 2.89(s, 3H), 2.26 (s, 3H) 1223

MS (ESI) m/z 655.38 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.89 (bs,1H), 9.74 (bs, 1H), 8.10 (s, 1H), 7.72 (s, 1H), 7.48-7.44 (m, 2H), 7.36(d, J = 2.4 Hz, 1H), 7.24 (d, J = 9.2 Hz, 1H), 4.37 (s, 4H), 4.02- 4.00(m, 2H), 3.91-3.75 (m, 2H), 3.54 (d, J = 10.4 Hz, 2H), 3.19 (d, J = 12.0Hz, 2H), 3.15-2.98 (m, 2H), 2.89 (s, 3H), 2.80 (q, J = 8.0 Hz, 2H), 2.29(s, 3H), 1.22 (t, J = 7.6 Hz, 3H) 1224

MS (ESI) m/z 656.30 [M +1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.93 (bs, 1H),8.05 (s, 1H), 7.52 (s, 1H), 7.46 (dd, J = 8.8, 2.4 Hz, 1H), 7.34 (d, J =2.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.95 (s, 1H), 4.36 (bs, 4H), 3.91(s, 3H), 3.75-3.50 (m, 2H), 3.20-2.70 (m, 6H), 2.26 (s, 3H), 2.24 (s,3H) 1225

MS (ESI) m/z 670.31 [M +1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.39 (bs, 1H),8.04 (s, 1H), 7.42 (dd, J = 8.0, 4.0 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H),7.20 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.63 (s, 1H), 4.34 (s, 4H),3.82-3.35 (m, 4H), 2.99 (s, 6H), 2.95-2.69 (m, 4H), 2.24 (s, 3H), 2.22(s, 3H) 1226

MS (ESI) m/z 655.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.93 (bs,1H), 8.09 (s, 1H), 7.46-7.44 (dd, J = 2.0, 8.8 Hz, 1H), 7.21- 7.16 (m,2H), 7.08 (s, 1H), 4.30 (bs, 4H), 3.78 (bs, 2H), 3.14 (m, 4H), 2.91 (bs,2H), 2.74 (s, 3H), 2.45 (s, 3H), 2.02 (s, 3H), 1.88 (s, 3H) 1228

MS (ESI) m/z 707.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 4Hz, 1H), 8.19 (s, 1H), 7.68 (s, 1H), 7.60-7.58 (dd, J = 2.4, 8.8 Hz,1H), 7.45 (t, J = 4 Hz, 2H), 7.37 (d, J = 8.8 Hz, 1H), 4.41 (bs, 2H),4.23 (bs, 2H), 3.86- 2.64 (m, 8H), 2.32 (s, 3H), 1.74 (s, 3H) 1237

MS (ESI) m/z 729.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 13.62 (bs, 1H),7.96 (s, 1H), 7.63-7.60 (dd, J = 2.4, 8.8 Hz, 1H), 7.52 (s, 1H), 7.43(d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 5.79 (d, J = 46.4 Hz,2H), 4.41 (bs, 2H), 4.26 (bs, 2H), 3.89 (t, J = 12.4 Hz, 2H), 3.56 (t, J= 10.4 Hz, 2H), 3.20 (t, J = 12.8 Hz, 2H), 3.09 (bs, 2H), 2.90 (s, 3H),2.39 (s, 3H), 1.88 (s, 3H) 1238

MS (ESI) m/z 741.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 13.98 (bs, 1H),7.93 (s, 1H), 7.62-7.60 ( m, 1H), 7.48 (s, 1H), 7.43 (bs, 1H), 7.37 (d,J = 8.8 Hz, 1H), 4.75 (s, 2H), 4.41 (bs, 2H), 4.25 (bs, 2H), 3.57 (t, J= 12.0 Hz, 2H), 3.44 (bs, 2H), 3.40 (s, 3H), 3.21 (t, J = 10.8 Hz, 2H),3.10 (bs, 2H), 2.90 (s, 3H), 2.39 (s, 3H), 1.89 (s, 3H) 1239

MS (ESI) m/z 733.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.02 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.27 (s, 1H), 7.94 (s, 1H), 7.60 (dd, J =8.8, 2.8 Hz 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H),7.36 (d, J = 8.8 Hz, 1H), 6.47-6.19 (m, 1H), 4.40 (s, 2H), 4.24 (s, 2H),3.70-3.50 (merged, 2H), 3.30-2.80 (m, 8H), 1.75 (s, 3H) 1241

MS (ESI) m/z 725.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.77 (bs,1H), 8.83 (d, J = 4.64 Hz, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.11 (dd, J= 8.9 Hz, 2.16 Hz, 1H), 7.48 (d, J = 4.6 Hz, 1H), 7.43 (s, 1H), 7.36 (d,J = 9.0 Hz, 1H), 4.74 (bs, 4H), 4.59 (bs, 1H), 4.41 (s, 2H), 4.25 (s,2H), 4.07 (bs, 2H), 3.54 (bs, 2H), 3.30 (bs, 2H), 2.93 (bs, 2H), 1.76(s, 3H) 1242

MS (ESI) m/z 739.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H),8.24 (s, 1H), 7.92 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 6 Hz,2H), 7.36 (d, J = 8.8 Hz, 1H), 4.78- 4.73 (m, 4H), 4.59 (bs, 1H), 4.40(s, 2H), 4.25- (s, 2H), 3.91 (bs, 4H), 3.29 (bs, 2H), 2.92 (bs, 2H),2.72 (s, 3H), 1.84 (s, 3H) 1243

MS (ESI) m/z 727.33 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H),8.84 (d, J = 4.8 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.62 (dd, J = 2.4,9.2 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.37(d, J = 8.8 Hz, 1H), 4.42 (t, J = 4.8 Hz, 2H), 4.26 (t, J = 4.8 Hz, 2H),3.95 (bs, 2H), 3.71 (m, 2H), 3.58 (m, 2H), 3.44 (m, 2H), 3.35 (s, 3H),3.12 (d, J = 10 Hz, 2H), 3.12 (t, J = 10 Hz, 2H), 1.77 (s, 3H) 1244

MS (ESI) m/z 663.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.71 (bs, 1H),8.73 (d, J = 4.4 Hz, 1H), 8.12 (s, 1H), 7.62 (s, 1H), 7.56 (dd, J = 8.8,2.4 Hz, 1H), 7.38-7.31 (m, 3H), 4.68 (s, 1H), 4.40 (s, 2H), 4.26 (s,2H), 3.86 (t, J = 12.0 Hz, 2H), 3.54 (d, J = 11.6 Hz, 2H), 3.22 (d, J =12.8 Hz, 2H), 3.15-3.00 (m, 2H), 2.91 (s, 3H), 1.82 (s, 3H) 1245

MS (ESI) m/z 664.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J =4.4 Hz, 1H), 8.41 (s, 1H), 8.10 (s, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H),7.56 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz,1H), 4.43-4.43 (m, 2H), 4.24 (s, 2H), 3.65- 3.49 (m, 2H), 2.99-2.89 (m,4H), 2.74 (s, 2H), 2.24 (s, 3H), 1.69 (s, 3H) 1246

MS (ESI) m/z 673.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H),8.08 (s, 1H), 7.56 (d, J = 7.84, 1H), 7.45 (s, 1H), 7.37-7.31 (m, 3H),4.40 (s, 2H), 4.27 (s, 2H), 3.72-3.51 (m, 2H), 2.90 (bs, 4H), 2.25 (s,5H), 1.83 (s, 3H) 1247

MS (ESI) m/z 673.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.01 (s, 1H), 7.58 (dd, J = 2.8, 8.8 Hz, 1H), 7.51 (s, 1H),7.41 (d, J = 4.8 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 6.8 Hz,1H), 4.39 (t, J = 4.8 Hz, 2H), 4.24 (t, J = 4.0 Hz, 2H), 3.62 (bs, 2H),2.81 (bs, 6H), 2.24 (s, 3H), 1248

MS (ESI) m/z 653.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H),8.06 (s, 1H), 7.52 (s, 1H), 7.31 (t, J = 9.9 Hz, 2H), 7.13 (s, 1H), 7.06(s, 1H), 4.36 (s, 2H), 4.26 (s, 2H), 3.91-3.42 (m, 2H), 3.22-2.71 (m,4H), 2.63- 2.21 (m, 5H), 2.12 (s, 3H), 1.86 (s, 3H) 1249

MS (ESI) m/z 653.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.73 (bs, 1H),8.66 (d, J = 4.8 Hz, 1H), 8.05 (s, 1H), 7.55 (dd, J = 8.8, 2.4 Hz, 1H),7.34-7.31 (m, 2H), 7.24 (d, J = 4.8 Hz, 1H), 7.13 (s, 1H), 4.41-4.34 (m,2H), 4.30- 4.20 (m, 2H), 3.87 (t, J = 11.6 Hz, 2H), 3.56 (d, J = 11.6Hz, 2H), 3.26 (d, J = 12.0 Hz, 2H), 3.15-3.00 (m, 2H), 2.91 (s, 3H),2.36 (s, 3H), 1.81 (s, 3H) 1250

MS (ESI) m/z 640.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.74 (bs, 1H),9.16 (s, 1H), 8.07 (s, 1H), 8.01 (d, J = 5.32 Hz, 1H), 7.62 (dd, J =8.9, 2.6 Hz, 1H), 7.46 (d, J = 2.6 Hz, 1H) 7.42 (d, J = 5.4 Hz, 1H) 7.36(d, J = 9.0 Hz, 1H), 4.43 (t, J = 4.9 Hz, 2H), 4.29 (t, J = 4.32 Hz,2H), 3.87 (t, J = 11.2 Hz, 2H), 3.55 (d, J = 11.6 Hz, 2H), 3.25 (d,12.36 Hz, 2H), 3.15-3.00 (m, 2H), 2.90 (s, 3H), 1.93 (s, 3H) 1251

MS (ESI) m/z 640.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H),8.84 (d, J = 4.5 Hz, 1H), 8.05 (s, 1H), 7.58 (dd, J = 9.0 Hz, 2.5 Hz,1H), 7.55 (d, J = 4.5 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H), 7.35 (d, J =8.9 Hz, 1H), 4.43 (t, J = 4.16 Hz, 2H), 4.27 (t, J = 4.36 Hz, 2H), 3.61(bs, 4H), 2.96 (bs, 4H), 2.24 (s, 3H), 1.88 (s, 3H) 1252

MS (ESI) m/z 667.36 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J =4.7 Hz, 1H),), 8.01 (s, 1H), 7.54-7.51 (dd, J = 8.8, J = 2.5 Hz, 1H),7.30 (m, 2H), 7.18 (d, J = 4.6 Hz, 1H), 4.37 (t, J = 12.7 Hz, 2H), 4.23(t, J = 3.4 Hz, 2H), 3.64 (m, 4H), 2.89 (m, 4H), 2.23 (s, 6H), 1.97 (s,3H), 1.79 (s, 3H) 1253

MS (ESI) m/z 671.22 [M +1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H),7.78 (d, J = 5.6 Hz, 1H), 7.57 (dd, J = 2.80, 8.8 Hz, 1H), 7.39 (d, J =2.8 Hz, 1H), 7.37 (d, J = 9.6 Hz, 1H), 7.34-7.31 (m, 2H), 5.59 (d, J =46.8 Hz, 2H), 4.36 (t, J = 4.4 Hz, 2H), 4.25 (t, J = 4.0 Hz, 2H), 3.61(bs, 2H), 2.93 (bs, 2H), 2.50 (bs, 2H), 2.25 (bs, 5H), 1.85 (s, 3H) 1254

MS (ESI) m/z 664.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.48 (s, 1H), 8.03 (s, 1H), 7.61 (dd, J = 2.4, 11.2 Hz,1H), 7.50 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.37 (d, J =8.8 Hz, 1H), 4.40 (bs, 2H), 4.26 (bs, 2H), 3.57 (m, 2H), 3.02 (m, 4H),2.60 (m, 2H), 2.24 (s, 3H), 1.76 (s, 3H) 1255

MS (ESI) m/z 612.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.99 (bs, 1H),68.63 (d, J = 4.8 Hz, 1H), 68.10 (s, 1H), 7.66 (d, J = 5.6 Hz, 1H), 7.54(dd, J = 8.7 Hz, 2.5 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.33-31 (m, 2H),7.21 (d, J = 4.4 Hz, 1H), 4.37 (t, J = 5.1 Hz, 2H), 4.27 (t, J = 4.5 Hz,2H), 3.45-3.43 (m, 2H), 3.32 (bs, 2H), 2.95 (s, 6H), 1.96 (s, 3H) 1256

MS (ESI) m/z 653.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J =4.8 Hz, 1H), 8.05 (s, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.55 (dd, J = 2.4,8.8 Hz, 1H), 7.42 (d, J = 5.6, Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.32(d, J = 8.8 Hz, 1H), 7.22 (d, J = 4.4 Hz, 1H), 4.38 (t, J = 4.4 Hz, 2H),4.25 (t, J = 5.2 Hz, 2H), 3.85 (s, 2H), 2.47 (m, 4H), 2.27 (m, 4H), 1.83(s, 3H), 1.23 (s, 3H) 1259

MS (ESI) m/z 666.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J =4.0 Hz 1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.58 (d, J = 6.4 Hz, 1H), 7.42(d, J = 9.2 Hz, 2H), 7.33 (d, J = 8.8 Hz 1H), 4.39 (s, 2H), 4.23 (s,2H), 3.67 (s, 2H), 2.32 (s, 6H), 1.68 (s, 3H) 1260

MS (ESI) m/z 638.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.28 (s, 1H),8.84 (d, J = 4.8 Hz, 1H), 8.47 (bs, 3H), 8.31 (s, 1H), 8.04 (s, 1H),7.61 (dd, J = 8.8, 2.4 Hz, 1H), 7.49 (d, J = 4.4 Hz, 1H), 7.44 (d, J =2.8 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 4.41 (bs, 2H), 4.27 (bs, 4H),1.74 (s, 3H) 1261

MS (ESI) m/z 713. 27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.25 (bs,1H), 9.60 (bs, 1H), 8.84 (d, J = 4.8 Hz, 1H), 8.21 (s, 1H), 7.95 (s,1H), 7.61 (dd, J = 2.4, 8.8 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.42 (d,J = 2.4 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 5.69 (bs, 1H), 4.41 (s, 2H),4.24 (s, 2H), 3.95-3.89 (m, 3H), 3.63-3.58 (m, 2H), 3.22-3.30 (m, 6H),2.96-2.89 (m, 4H), 1.75 (s, 3H) 1262

MS (ESI) m/z 749.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.37 (bs,1H), 8.84 (d, J = 4.8 Hz, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.59 (dd, J =2.4, 8.8 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H),7.36 (d, J = 9.2 Hz, 1H), 4.40 (s, 2H), 4.23 (s, 2H), 3.96 (m, 2H), 3.48(m, 4H), 3.24 (m, 1H), 2.96 (s, 3H), 1.72 (s, 3H) 1263

MS (ESI) m/z 682.0 [M + 1]+; ; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.90 (s, 1H), 7.63-7.56 (m, 1H), 7.46-7.38 (m, 2H), 7.35 (d, J = 8.96Hz, 1H), 4.49-4.32 (m, 2H), 4.31-4.18 (m, 2H), 3.70-3.66 (m, 1H),3.26-3.22 (m, 2H), 2.69 (s, 3H), 2.32-2.22 (m, 2H), 2.22-2.09 (m, 2H),2.07 (s, 3H), 1.80 (s, 3H) 1269

MS (ESI) m/z 699.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.12 (bs,1H), 8.94 (s, 1H), 8.91 (d, J = 4.8 Hz, 1H), 8.15 (s, 1H), 7.75 (d, J =9.2 Hz, 1H), 7.57 (d, J = 4.4 Hz, 1H), 7.49 (bs, 2H), 4.18 (t, J = 6.0Hz, 2H), 3.87 (bs, 2H), 3.54 (d, J = 12.4 Hz, 2H), 3.33 (bs, 2H), 3.22(d, J = 11.6 Hz, 2H), 3.08 (bs, 2H), 2.90 (s, 3H), 2.52 (s, 3H) 1270

MS (ESI) m/z 691.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.11 (bs,1H), 8.7 (d, J = 4.7 Hz, 1H), 8.62 (s, 1H), 8.26 (s, 1H), 7.76 (d, J =8.1 Hz, 1H), 7.72-7.66 (m, 2H), 7.25 (d, J = 4.7 Hz, 1H), 5.01- 4.45 (m,2H), 4.20-3.82 (m, 4H), 3.70-3.45 (m, 2H), 2.88 (s, 3H), 2.16 (s, 3H)1271

MS (ESI) m/z 691.28 [M + 1]+; ; 1H NMR (400 MHz, DMSO-d6) δ 13.75 (bs,1H), 9.75 (bs, 1H), 8.74 (d, J = 4.8 Hz, 1H), 8.11 (s, 1H), 7.76-7.69(m, 2H), 7.65 (s, 1H), 7.58 (d, J = 4.8 Hz, 1H), 4.86 (s, 2H), 3.89 (t,J = 22.4 Hz, 2H), 3.59 (d, J = 11.2 Hz, 2H), 3.30 (d, J = 11.2 Hz, 2H),3.11 (d, J = 8 Hz, 2H), 2.92 (bs, 3H), 2.64 (s, 3H), 2.22 (s, 3H) 1272

MS (ESI) m/z 711.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.8 (d, J =4.8 Hz, 1H), 8.09 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.50 (d, J= 4.8 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz 1H), 4.42(bs, 2H), 4.28 (bs, 2H), 4.08-3.55 (m, 6H), 2.87 (s, 3H), 2.37 (s, 3H),1.82 (s, 3H) 1275

MS (ESI) m/z 724.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 13.73 (bs, 1H),8.17 (s, 1H), 7.96 (s, 1H), 7.62-7.59 (dd, J = 2.8, 9.2 Hz, 1H),7.47-7.44 (m, 2H), 7.37 (d, J = 8.8 Hz, 1H), 4.41 (bs, 2H), 4.24 (bs,2H), 3.43-3.40 (m, 2H), 3.23-2.86 (m, 6H), 2.73 (s, 3H), 2.02 (bs, 1H),1.79 (bs, 5H), 1.64-1.55 (m, 2H), 1.37 (t, J = 7.6 Hz, 3H) 1276

MS (ESI) m/z 710.27 [M + 1]+; ; 1H NMR (400 MHz, DMSO-d6) δ 13.70 (bs,1H), 8.45 (bs, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.61-7.59 (dd, J = 6.8,8.8 Hz, 1H), 7.46-7.43 (m, 2H), 7.37 (d, J = 8.8 Hz, 1H), 4.41 (bs, 2H),4.24 (bs, 2H), 3.30 (m, 2H), 3.06-2.98 (m, 4H), 2.84 (m, 2H), 2.08 (bs,1H), 1.79 (s, 3H), 1.75 (d, J = 13.6 Hz, 2H), 1.60 (t, J = 10.0 Hz, 2H),1.37 (t, J = 7.6 Hz, 3H) 1283

MS (ESI) m/z 682.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.06 (bs,1H), 8.79 (d, J = 5.2 Hz, 1H), 7.97 (d, J = 5.2 Hz, 1H), 7.61 (dd, J =2.8, 9.2 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.9 (d, J = 2.4 Hz, 1H),7.38 (d, J = 9.2 Hz, 1H), 4.42 (bs, 2H), 4.27 (bs, 2H), 4.20 (d, J = 6.0Hz, 2H), 4.02 (d, J = 8.0 Hz, 2H), 3.95 (bs, 1H), 3.38 (d, J = 5.6 Hz,2H), 2.85 (d, J = 4.8 Hz, 3H), 2.33 (s, 3H), 1.88 (s, 3H) 1286

MS (ESI) m/z 714.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.23 (bs,1H), 8.14 (s, 1H), 7.52 (dd, J = 8.8 Hz, 2.5 Hz, 1H), 7.27-7.25 (m, 2H),7.23- 7.21 (m, 2H), 4.34-4.33 (m, 2H), 4.27-4.25 (m, 2H), 3.87 (t, J =12.3 Hz, 2H), 3.55-3.53 (m, 2H), 3.18- 3.15 (m, 2H), 3.08-3.06 (m, 2H),2.89 (s, 3H), 2.04 (s, 3H), 1.83 (s, 3H) 1287

MS (ESI) m/z 704.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.60 (dd, J = 8.8 Hz, 2.4 Hz,1H), 7.49 (d, J = 4.4 Hz, 1H), 7.42-7.36 (m, 2H), 4.41 (bs, 6H), 4.24(s, 2H), 3.31 (d, J = 6.4 Hz, 2H), 3.21 (d, J = 4.8 Hz, 2H), 1.81 (s,3H) 1288

MS (ESI) m/z 706.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.4 Hz 1H), 8.21 (s, 1H), 7.98 (s, 1H) 7.59 (dd, J = 8.9, 2.6 Hz, 1H),7.49 (d, J = 4.8 Hz 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 6.18-6.46 (m, 1H), 4.41 (t, J = 6.02 Hz, 2H), 4.25 (t, J = 8.0 Hz,2H), 3.39 (s, 4H), 3.09 (s, 2H), 2.73 (s, 3H), 1.77 (s, 3H) 1259

MS (ESI) m/z 620.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (bs,1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.67-7.62 (m, 3H), 7.51 (bs, 2H), 7.37(bs, 1H), 5.02 (s, 2H), 3.87-3.45 (m, 4H), 3.21-2.91 (m, 4H), 3.02 (bs,3H), 2.85 (bs, 3H) 1291

MS (ESI) m/z 709.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.4 Hz, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.60 (dd, J = 6.4 Hz, 2.4 Hz,1H), 7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (d, J =8.8 Hz, 1H), 4.40 (s, 2H), 4.24 (s, 2H), 3.85 (s, 4H), 3.29 (bs, 4H),3.12 (bs, 1H), 1.76 (s, 3H), 1.01 (s, 2H), 0.85 (s, 2H) 1292

MS (ESI) m/z 759.38 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.30 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.60 (dd, J =6.4, 9.2 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H),7.36 (d, J = 8.8 Hz, 1H), 4.40 (s, 2H), 4.24 (s, 2H), 3.85-3.52 (m, 5H),3.02 (m, 8H), 1.75 (m, 3H) 1293

MS (ESI) m/z 765.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.26 (bs,1H), 8.82 (d, J = 4.8 Hz, 1H), 8.28 (s, 1H), 7.93 (s, 1H), 7.59 (d, J =8.8 Hz, 1H), 7.46 (d, J = 4.4 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 10.8Hz, 1H), 4.39 (bs, 2H), 4.23 (bs, 2H), 3.63 (bs, 2H), 3.31 (bs, 2H),2.95 (m, 4H), 2.60 (t, J = 7.2 Hz, 4H), 1.71 (s, 3H) 1298

MS (ESI) m/z 650.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.06 (bs,1H), 8.75 (d, J = 4.8 Hz, 1H), 8.57 (s, 1H), 8.14 (s, 1H), 7.77 (d, J =8.0 Hz, 1H), 7.70-7.66 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 4.88 (s, 2H),3.38-3.23 (m, 4H), 3.18-3.08 (m, 2H), 2.78 (s, 6H), 2.16 (s, 3H) 1372

MS (ESI) m/z 606.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.63 (dd, J =5.0, 0.8 Hz, 1H), 8.38 (d, J = 1.7 Hz, 1H), 8.26 (dd, J = 1.7, 0.8 Hz,1H), 8.03 (dd, J = 1.7, 0.8 Hz, 1H), 7.70 (dd, J = 5.0, 1.8 Hz, 1H),7.57-7.39 (m, 2H), 7.27 (d, J = 8.9 Hz, 1H), 4.40 (s, 4H), 3.39 (s, 3H),2.23 (s, 3H) 1374

MS (ESI) m/z 628.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J =1.7 Hz, 1H), 8.25 (s, 3H), 7.99 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 8.9,2.7 Hz, 1H), 7.45 (s, 1H), 7.39-7.34 (m, 2H), 4.41 (d, J = 5.1 Hz, 2H),4.27 (t, J = 5.1 Hz, 2H), 3.41 (d, J = 6.0 Hz, 2H), 3.28 (t, J = 6.5 Hz,2H), 1.83 (s, 3H) 1375

MS (ESI) m/z 624.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H),8.83 (d, J = 4.7 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H), 7.95 (s, 1H), 7.81(d, J = 1.6 Hz, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.45-7.39 (m, 2H),7.35 (d, J = 9.0 Hz, 1H), 6.92 (s, 1H), 4.40 (d, J = 5.0 Hz, 2H), 4.25(t, J = 4.9 Hz, 2H), 1.74 (s, 3H) 1376

MS (ESI) m/z 714.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H),7.95 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.46-7.40 (m, 2H), 7.36(d, J = 9.0 Hz, 1H), 4.40 (d, J = 5.0 Hz, 2H), 4.25 (s, 2H), 3.91 (s,2H), 2.70 (s, 5H), 2.58 (s, 2H), 1.83 (s, 3H) 1377

MS (ESI) m/z 746.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H),8.16 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.45-7.34 (m, 3H), 5.49(d, J = 22.9 Hz, 2H), 4.58 (t, J = 13.1 Hz, 2H), 4.42 (s, 2H), 4.29 (s,2H), 3.82 (s, 2H), 2.72 (s, 3H), 1.84 (s, 3H) 1380

MS (ESI) m/z 690.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.60-8.48 (m,1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.60 (dd, J =8.9, 2.8 Hz, 1H), 7.52-7.42 (m, 3H), 7.36 (d, J = 9.0 Hz, 1H), 4.50-4.34(m, 2H), 4.27 (d, J = 5.4 Hz, 2H), 2.72 (s, 3H), 2.10 (s, 3H), 1.81 (s,3H) 1381

MS (ESI) m/z 694.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H),8.76-8.65 (m, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.73 (t, J = 5.5 Hz, 1H),7.60 (dd, J = 8.9, 2.6 Hz, 1H), 7.49-7.40 (m, 2H), 7.37 (d, J = 9.0 Hz,1H), 4.50-4.18 (m, 4H), 2.72 (s, 3H), 1.87 (s, 3H) 1383

MS (ESI) m/z 708.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H),8.28 (s, 1H), 8.05 (s, 1H), 7.98-7.90 (m, 1H), 7.60 (dd, J = 8.9, 2.7Hz, 1H), 7.47-7.40 (m, 2H), 7.37 (d, J = 9.0 Hz, 1H), 4.42 (t, J = 5.0Hz, 2H), 4.29 (d, J = 4.9 Hz, 2H), 2.73 (s, 3H), 2.58 (d, J = 2.9 Hz,3H), 1.88 (s, 3H) 1384

MS (ESI) m/z 728.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J =9.9 Hz, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.60(dd, J = 8.9, 2.7 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.36(d, J = 9.0 Hz, 1H), 4.53-4.20 (m, 4H), 2.72 (s, 3H), 1.88 (s, 3H) 1388

MS (ESI) m/z 708.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.63-8.59 (m,1H), 8.33 (s, 1H), 8.11 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.50(d, J = 10.7 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.36 (d, J= 9.0 Hz, 1H), 4.53-4.02 (m, 4H), 2.72 (s, 3H), 2.62 (s, 3H), 1.85 (s,3H) 1389

MS (ESI) m/z 706.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H),9.47 (s, 1H), 9.18 (s, 1H), 8.23 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz,1H), 7.49 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H),7.19 (s, 1H), 4.53 (t, J = 5.2 Hz, 2H), 4.15 (t, J = 5.2 Hz, 2H), 2.67(d, J = 0.7 Hz, 3H), 2.33 (s, 3H), 2.29 (s, 3H) 1391

MS (ESI) m/z 711.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H),7.93 (s, 1H), 7.58 (dd, J = 8.9, 2.7 Hz, 1H), 7.39-7.31 (m, 2H), 7.28(s, 1H), 4.40 (s, 2H), 4.26 (s, 2H), 3.87 (s, 5H), 3.57 (d, J = 11.7 Hz,2H), 3.27 (d, J = 12.9 Hz, 2H), 3.09 (d, J = 10.7 Hz, 2H), 2.91 (d, J =4.2 Hz, 3H), 2.66 (s, 3H), 1.83 (s, 3H) 1392

MS (ESI) m/z 740.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H),7.93 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J =2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 5.35 (s, 1H), 4.41 (t, J = 5.0Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H), 3.97 (t, J = 12.1 Hz, 2H), 3.79 (t, J= 5.2 Hz, 2H), 3.64 (d, J = 11.8 Hz, 2H), 3.15 (dd, J = 29.0, 12.1 Hz,4H), 2.71 (s, 3H), 2.43 (s, 3H), 1.97 (s, 3H) 1393

[01858] MS (ESI) m/z 741.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.59(s, 2H), 7.93 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H),7.41 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.42 (t, J = 5.6 Hz,4H), 4.26 (t, J = 5.0 Hz, 2H), 3.16 (s, 4H), 3.00 (s, 2H), 2.82 (s, 4H),2.70 (s, 3H), 2.40 (s, 3H), 1.92 (s, 3H) 1394

MS (ESI) m/z 696.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H),9.59 (s, 1H), 8.15 (d, J = 5.8 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.61(dd, J = 8.9, 2.7 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.37(d, J = 9.0 Hz, 1H), 4.42 (t, J = 5.0 Hz, 2H), 4.35-4.18 (m, 3H), 4.01(dt, J = 22.5, 10.9 Hz, 2H), 3.11 (d, J = 8.1 Hz, 1H), 3.01 (q, J = 7.5Hz, 2H), 2.86 (dd, J = 11.5, 5.1 Hz, 2H), 1.81 (s, 3H), 1.36 (t, J = 7.5Hz, 3H) 1416

MS (ESI) m/z 711.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H),7.93 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J =2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 4.9 Hz, 2H), 4.26(t, J = 5.0 Hz, 2H), 3.86 (t, J = 12.3 Hz, 2H), 3.56 (d, J = 11.4 Hz,3H), 3.20 (d, J = 12.6 Hz, 2H), 3.09 (q, J = 11.2 Hz, 2H), 2.95-2.87 (m,3H), 2.71 (s, 3H), 2.42 (s, 3H), 1.96 (s, 3H) 1417

MS (ESI) m/z 708.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H),8.04-7.95 (m, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.45 (s, 1H), 7.41(d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 6.54 (s, 1H), 5.91 (s,1H), 4.42 (t, J = 5.1 Hz, 2H), 4.34- 4.21 (m, 2H), 4.13 (d, J = 17.4 Hz,1H), 3.84 (d, J = 16.9 Hz, 1H), 3.70-3.57 (m, 1H), 3.40-3.27 (m, 1H),3.02-2.89 (m, 3H), 2.71 (s, 3H), 2.64 (s, 1H), 2.41 (s, 3H), 1.98 (s,3H) 1420

MS (ESI) m/z 723.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H),7.78 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.42-7.40 (m, 2H), 7.36(d, J = 8.9 Hz, 1H), 4.70 (s, 2H), 4.61 (s, 2H), 4.49-4.39 (m, 2H), 4.38(t, J = 5.0 Hz, 2H), 4.27-4.17 (m, 4H), 2.82 (d, J = 5.2 Hz, 3H), 2.70(s, 3H), 1.92 (s, 3H) 1570

MS (ESI) m/z 715.47 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =5.2 Hz, 1H), 8.66 (s, 1H), 7.93 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H),7.70-7.66 (m, 2H), 7.56 (d, J = 4.4 Hz, 1H), 4.82 (s, 2H), 4.73-4.41 (m,8H), 3.05 (bs, 1H), 2.11 (s, 3H), 0.77 (bs, 4H) 1612

MS (ESI) m/z 775.53 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 with D20) δ 8.75(d, J = 4.68 Hz 1H), 8.10 (d, J = 9.44 Hz, 1H), 8.03 (s, 1H), 7.53 (dd,J = 2.56, 8.92 Hz, 1H), 7.34 (d, J = 2.60 Hz, 1H), 7.31 (d, J = 4.68 Hz,1H), 7.27 (d, J = 9.0 Hz, 1H), 4.35 (bs, 2H), 4.25-4.20 (m, 6H), 3.55(bs, 2H), 2.93 (bs, 2H), 2.50 (bs, 2H), 2.20 (s, 5H), 1.58 (s, 3H), 1.27(t, J = 7.04 Hz, 6H) 1613

MS (ESI) m/z 719.52 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 with D20) δ 8.60(d, J = 4.00 Hz 1H), 8.14 (s, 1H), 7.97 (d, J = 8.80 Hz, 1H), 7.49 (dd,J = 2.40, 8.80 Hz, 1H), 7.34 (d, J = 2.00 Hz, 1H), 7.24 (d, J = 9.20 Hz,1H), 7.13 (d, J = 4.80 Hz, 1H), 4.32 (bs, 2H), 4.21 (bs, 2H), 3.67 (bs,2H), 3.11 (bs, 4H), 2.76 (bs, 2H), 2.59 (s, 3H), 1.74 (s, 3H) 1614

MS (ESI) m/z 801.60 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 with D20) δ 8.75(d, J = 4.80 Hz, 1H), 8.09 (d, J = 9.60 Hz, 1H), 8.03 (s, 1H), 7.53 (dd,J = 2.40, 8.80 Hz, 1H), 7.33- 7.30 (m, 2H), 7.26 (d, J = 8.80 Hz, 1H),4.34 (s, 2H), 4.23-4.19 (m, 6H), 3.50 (bs, 2H), 2.79 (bs, 5H), 1.67 (bs,2H), 1.58 (s, 3H), 1.27 (t, J = 6.80 Hz, 6H), 0.43 (bs, 2H), 0 .35 (bs,2H) 1615

MS (ESI) m/z 745.50 [M + 1]+; 1H NMR (400 MHz, DMSO-d6 with D20) δ 8.63(d, J = 4.80 Hz, 1H), 8.12 (s, 1H), 7.98 (d, J = 8.80 Hz, 1H), 7.49 (dd,J = 2.40, 8.80 Hz, 1H), 7.32 (d, J = 2.40 Hz, 1H), 7.23 (d, J = 9.20 Hz,1H), 7.14 (d, J = 4.4 Hz, 1H), 4.31 (s, 2H), 4.20 (s, 2H), 3.49 (bs,3H), 2.84 (bs, 4H), 1.75 (bs, 2H), 1.70 (s, 3H), 0.44 (d, J = 6.00 Hz,2H), 0.38 (bs, 2H) 1619

MS (ESI) m/z 642.01[M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H),7.89 (s, 1H), 7.59 (dd, J = 2.60, 8.88 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J= 2.64 Hz, 1H), 7.36 (d, J = 8.96 Hz, 1H), 4.39 (t, J = 4.68 Hz, 2H),4.23 (t, J = 4.64 Hz, 2H), 2.94 (s, 6H), 2.70 (s, 3H), 1.81 (s, 3H) 1899

MS (ESI) m/z 571 [M + 1]; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.43(d, J = 16.6 Hz, 2H), 8.11 (s, 1H), 7.79 (bs, 1H), 7.60 (s, 1H), 7.46(m, 2H), 7.35 (m, 1H), 4.40 (s, 2H), 4.20 (s, 2H), 3.89 (s, 1H) 1900

MS (ESI) m/z 599.1 [M + 1] 1901

MS (ESI) m/z 579.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.48 Hz, 1H), 8.59 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.69 (d, J = 6.04 Hz, 2H), 7.56 (d, J = 4.48 Hz, 1H), 4.88 (s,2H), 2.10 (s, 3H) 1902

MS (ESI) m/z 627.8 [M + 1]+ 1903

MS (ESI) m/z 603.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.38 (bs, 1H), 8.28 (s, 1H), 8.01 (bs, 1H), 7.63 (d, J =8.4 Hz, 1H), 7.54 (d, J = 11.4 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 4.43(t, J = 4.4 Hz, 2H), 4.25 (t, J = 4.4 Hz, 2H), 1.73 (s, 3H) 1904

MS (ESI) m/z 619.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J =4.4 Hz, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.60 (dd, J = 8.8, 2.6 Hz, 1H),7.51 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 8.8 Hz,1H), 4.41 (t, J = 4.7 Hz, 2H), 4.25 (t, J = 4.7 Hz, 2H), 1.69 (s, 3H)1905

MS (ESI) m/z 633.04 [M + 1]+ 1906

1907

MS (ESI) m/z 656.15 [M + 1] 1908

MS (ESI) m/z 724.6 [M + 1]+ 1909

MS (ESI) m/z 708.1 [M + 1]+ 1910

MS (ESI) m/z 690.3 [M + 1]+ 1911

MS (ESI) m/z 722.0 [M + 1]+ 1912

MS (ESI) m/z 773.3 [M + 1]+ 1913

MS (ESI) m/z 850.3 [M + 1]+ 1914

1915

1916

1917

1918

1919

1920

1921

1922

1923

1924

1925

1926

1927

1928

1929

1930

1931

1932

1933

1934

1994

2015

2016

2018

2019

MS (ESI) m/z 626.05 [M + 1]+ 2028

MS (ESI) m/z 624.0 [M + 1]+ 2036

MS (ESI) m/z 747.2 [M + 1]+ 2037

MS (ESI) m/z 615.1 [M + 1]+

Example 3. General Methods for Synthesizing Other Compounds

Compounds in Table 3 can be synthesized using methods described inExample 3. Many of the reactions described in Examples 1 and 2 were alsoused to synthesize compounds in Table 3.

Example 3A. Methods of Synthesizing the Left-Hand Side Example 3A.1

3-amino-6-chloropicolinamide (1, 3.00 g, 16.6 mmol) is dissolved in1,1,1-triethoxyethane (45 mL, 16.6 mmol) in a flame dried round bottomflask equipped with a stir bar. The reaction mixture heated to 110° C.for 90 min then cooled to 10° C. and diluted with cold ether. The solidsare filtered and washed several times with cold ether. Drying the solidsin vacuo afforded 6-chloro-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one (2).

6-chloro-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one (2, 1.00 g, 5.1 mmol)is dissolved in DMSO (30 mL) in a round bottomed flask equipped with astir bar. The reaction mixture is stirred at 10° C. whilebis(trifluoromethylsulfonyl)zinc (4.23 g, 12.8 mmol) is added in 1portion. tert-Butyl hydroperoxide (3.53 mL, 19.2 mmol) is then addeddropwise via addition funnel. After 5 min the reaction mixture is warmedto room temperature and after an additional 5 min it is warmed to 50° C.for 6.5 h. The reaction mixture is cooled to room temperature and thenthe reaction mixture is diluted with saturated sodium bicarbonate andethyl acetate. The layers are separated and the aqueous phase extractedwith ethyl acetate three times. The combined organic material is washedwith brine and dried over magnesium sulfate. The solids are filtered andsolvent removed in vacuo to afford6-chloro-2-methyl-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one(3).

Example 3A.2

A solution of6-bromo-2-methyl-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one (1,0.3 g, 0.977 mmol), sodium thiomethoxide (0.102 g, 1.46 mmol),N,N-diisopropylethylamine (0.378 g, 2.93 mmol), and Xantphos (0.056 g,0.097 mmol) in toluene (3 mL) is degassed for 10 min using argon. Then,tris(dibenzylideneacetone)dipalladium(0) (0.042 g, 0.048 mmol) is addedand the mixture is degassed again with argon for 5 min. The reactionmixture is stirred at 90° C. for 2 h. After this time, the reactionmixture is diluted with water and extracted with ethyl acetate. Theorganic layer is dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness under reduced pressure to obtain the crudeproduct. This is purified by flash column chromatography using silicagel (100-200 mesh) and 60-80% ethyl acetate in hexanes as eluent toafford2-methyl-6-(methylthio)-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one(2).

To a solution of2-methyl-6-(methylthio)-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one(2, 0.2 g, 0.727 mmol) in ethyl acetate (4.0 mL) and water (1.0 mL) isadded ruthenium(III) chloride (0.007 g, 0.0363 mmol) followed by sodiumperiodate (0.929 g, 4.36 mmol). The reaction mixture is stirred at roomtemperature for 30 min. After this time, the reaction mixture isfiltered and the filtrate is concentrated under reduced pressure toobtain the crude product. This is purified by pentane wash to afford2-methyl-6-(methylsulfonyl)-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one(3).

Example 3A.3

6-chloro-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one (1, 1.00 g, 5.1 mmol)is dissolved in dimethyl sulfoxide (30 mL) in a round bottomed flaskequipped with a stir bar. The reaction mixture is stirred at 10° C.while bis(trifluoromethylsulfonyl)zinc (4.23 g, 12.8 mmol) is added in 1portion. tert-Butyl hydroperoxide (3.53 mL, 19.2 mmol) is then addeddropwise via addition funnel. After 5 min the reaction mixture is warmedto room temperature and after an additional 5 min it is warmed to 50° C.for 6.5 h. The reaction mixture is cooled to room temperature and thendiluted with saturated aqueous sodium bicarbonate and ethyl acetate. Thelayers are separated and the aqueous phase extracted with ethyl acetatethree times. The combined organic material is washed with brine anddried over magnesium sulfate. The solids are filtered and solventremoved in vacuo to afford a mixture of6-chloro-2-methyl-8-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one(2).

Example 3A.4

5-bromo-6-chloro-3-(4-methoxybenzyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(1, 50 mg, 0.13 mmol) and copper(I) iodide (26.5 mg, 0.139 mmol) arecombined in a sealable vessel with a stirbar and suspended in 1 mL2-(dimethylamino)ethan-1-ol (1a). The resulting mixture is sparged withargon for 3 min and then sealed, vigorously stirred, and heated at 100°C. After 10 min LCMS shows complete consumption of the startingmaterial. The mixture is cooled to room temperature and concentrated.The residue is taken up in MeCN/DMSO and purified by prep-HPLC(MeCN/water+0.1% TFA) to afford6-chloro-5-(2-(dimethylamino)ethoxy)-3-(4-methoxybenzyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one(2).

Example 3A.5

To a solution of 3-bromo-2-chloroisonicotinic acid (1, 3.0 g, 12.76mmol) in dichloromethane (20 mL) is added N,N-dimethylformamide (0.09mL, 1.27 mmol) at 0° C. followed by oxalyl chloride (1.7 mL, 19.14mmol). Then the reaction mixture is stirred at −25° C. for 2 h. Aftercompletion, the reaction mixture is evaporated to dryness under reducedpressure. Crude reaction mixture is diluted with dichloromethane (10 mL)and poured into ice cold aqueous ammonia in a drop wise manner.Precipitated solid is filtered through sintered funnel and dried undervacuum to afford 3-bromo-2-chloroisonicotinamide (2).

To a solution of 3-bromo-2-chloroisonicotinamide (2, 2.5 g, 10.68 mmol),pentamethylcyclopentadienylrhodium(III) chloride dimer (0.33 g, 0.53mmol) and cesium acetate (1.02 g, 5.34 mmol) in 1,2-dichloroethane (25mL) is added tert-butyl 2-diazo-3-oxobutanoate (2b, 2.96 g, 16.00 mmol)to the reaction mixture at room temperature under nitrogen atmosphere.Reaction mixture is heated to 100° C. for 16 h. After completion, thereaction mixture is cooled to room temperature, concentrated to drynessunder reduced pressure followed by washing with ether and pentane toafford tert-butyl8-bromo-7-chloro-3-methyl-1-oxo-1,2-dihydro-2,6-naphthyridine-4-carboxylate(3).

To tert-butyl8-bromo-7-chloro-3-methyl-1-oxo-1,2-dihydro-2,6-naphthyridine-4-carboxylate(3, 3.0 g, 8.00 mmol) 30% hydrobromic acid in acetic acid (30 mL) isadded and the reaction mixture is stirred at 80° C. for 16 h. Aftercompletion, the reaction is quenched with ice cold water and extractedwith ethyl acetate. The organic layer is washed with cold water, driedover anhydrous sodium sulfate, filtered and concentrated to drynessunder reduced pressure to afford crude8-bromo-7-chloro-3-methyl-2,6-naphthyridin-1(2H)-one (4).

Example 3A.6

4-Amino-6-methylnicotinic acid (1, 700 mg, 4.6 mmol) and ammoniumacetate (1.58 g, 20.6 mmol) are dissolved in 1,4-dioxane (8 mL) andacetic anhydride (1a, 1.74 mL, 18.4 mmol) in an oven-dried microwavevial equipped with a stir bar. The reaction mixture is stirred at 200°C. in a microwave reactor for 24 h. Solvent is removed in vacuo. Ethylacetate is added and the precipitate is filtered and washed once withethyl acetate. Solids are dried under vacuum to afford2,7-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (2).

2,7-Dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (2, 92 mg, 0.50 mmol) and1-(chloromethyl)-4-methoxybenzene (2a, 0.08 mL, 0.60 mmol) are dissolvedin N,N dimethylformamide (2.5 mL) in an oven-dried screw capped vialequipped with a stir bar. The reaction mixture is stirred at roomtemperature while potassium carbonate (137.9 mg, 1 mmol) and potassiumiodide (16.5 mg, 0.10 mmol) are added sequentially. After 20 h thereaction mixture is diluted with ethyl acetate and then washed with a50:50 water:brine solution and then twice more with 100% brine. Theorganic material is then dried over magnesium sulfate, filtered andsolvent removed in vacuo. Purification via silica gel chromatography(25-100% ethyl acetate in hexanes) afforded the3-(4-methoxybenzyl)-2,7-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (3).

3-(4-Methoxybenzyl)-2,7-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (3, 109mg, 0.37 mmol) is dissolved in dichloromethane (2 mL) in an oven-driedscrew capped vial equipped with a stir bar. The reaction mixture isstirred at 0° C. while is 3-chlorobenzenecarboperoxoic acid (84 mg, 0.49mmol) added slowly. After 5 min the reaction mixture is warmed to roomtemperature. After 3 h the reaction mixture is diluted with saturatedaqueous sodium bicarbonate and dichloromethane. The layers are separatedand the aqueous phase extracted with dichloromethane once. The combinedorganic material is washed with brine and dried over magnesium sulfate.The solids are filtered and solvent removed in vacuo to afford3-(4-methoxybenzyl)-2,7-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine6-oxide (4).

3-(4-Methoxybenzyl)-2,7-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine6-oxide (4, 25 mg, 0.06 mmol) is dissolved in dichloromethane (1 mL) inan oven-dried screw capped vial equipped with a stir bar. The reactionmixture is stirred at 25° C. and then trimethylsilyl cyanide (0.04 mL,0.32 mmol) and N,N-dimethylcarbamoyl chloride (0.03 mL, 0.32 mmol) areadded sequentially. After 45 min the reaction mixture is warmed to 45°C. After 14 h the reaction mixture is cooled to room temperature andsolvent is removed in vacuo. Purification via silica gel chromatography(25-80% ethyl acetate in dichloromethane) afforded3-(4-methoxybenzyl)-2,7-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine-5-carbonitrile(5).

Example 3A.7

A solution of 5-chloro-6-(trifluoromethyl)pyridin-2-amine (1, 100 mg,0.51 mmol) and N-Bromosuccinimide (91 mg, 0.51 mmol) in MeCN (4 mL)heated at 80° C. for 1 hr. After this time, the reaction mixture isconcentrated, diluted with water and extracted with ethyl acetate. Thecombined organic layer is washed with water and brine solution, driedover sodium sulfate and concentrated. The crude material then directlyloaded on an Isco loading column. Purified by column chromatographyusing 5 to 40% ethyl acetate in hexane as eluent and product elutedaround 20% ethylacetate/hexane. The desired fractions are concentratedunder reduced pressure to afford3-bromo-5-chloro-6-(trifluoromethyl)pyridin-2-amine (2).

A solution of 3-bromo-5-chloro-6-(trifluoromethyl)pyridin-2-amine (2, 50mg, 0.18 mmol) and dicyanozinc (24 mg, 0.19 mmol) in NMP (3 mL) ispurged with argon-gas for 5-min, then Pd(PPh3)4 (21 mg, 0.018 mmol) isadded. The mixture is heated at 120° C. for 30 min in microwave. Aftercompletion, the reaction mixture is directly loaded on the silicacolumn. Purified by column chromatography using 0 to 20% methanol indichloromethane as eluent and product eluted around 10%methanol/dichloromethane. The desired fractions are concentrated underreduced pressure to afford2-amino-5-chloro-6-(trifluoromethyl)nicotinonitrile (3).

2-amino-5-chloro-6-(trifluoromethyl)nicotinonitrile (3, 550 mg, 2.5mmol) is dissolved in concentrated sulfuric acid (1 mL) in a roundbottom flask, and the mixture is stirred at 90° C. for 15 min. Afterthis time, the reaction stopped and the mixture is cooled to roomtemperature. The reaction mixture is poured into ice-water and adjustedto pH 8 with saturated sodium hydrogen carbonate solution. Theprecipitate is collected by filtration and washed with cold water anddried in high vacuum to afford2-amino-5-chloro-6-(trifluoromethyl)nicotinamide (4).

A solution of 2-amino-5-chloro-6-(trifluoromethyl)nicotinamide (4, 65mg, 0.27 mmol), 1,1,1-triethoxyethane (0.13 mL, 1.09 mmol) and ethanol(2 mL) in a vial is heated to 120° C. in oil bath for 3 h. After thistime, the reaction mixture is diluted with 50% DMSO/MeOH, filtered andthe crude is purified by HPLC (C₁₈, prep column, 5-35% MeCN/water+0.1%TFA) to afford6-chloro-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one(5).

Example 3A.8

A solution of 2,6-dichloro-4-(trifluoromethyl)pyridine (1, 10.0 g, 4.6mmol), ammonium hydroxide (50 mL) is heated at 180° C. for 4 h. Aftercompletion, the reaction mixture is filtered, washed with water & driedto afford 6-chloro-4-(trifluoromethyl)pyridin-2-amine (2).

To a mixture of 6-chloro-4-(trifluoromethyl)pyridin-2-amine (2, 2.2 g,1.0 mmol) in phosphorous oxychloride (5 mL),3-acetyldihydrofuran-2(3H)-one (2a, 0.256 g, 2.0 mmol) is added at roomtemperature followed by heating and stirring at 20° C. for 1.5 h. Aftercompletion, the reaction mixture is poured into crushed ice & extractedwith ethyl acetate. Organic layer is dried over anhydrous sodium sulfateand concentrated to dryness under reduced pressure to afford6-chloro-3-(2-chloroethyl)-2-methyl-8-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(3).

Example 3A.9

To a solution of3-methyl-1-oxo-6-(trifluoromethyl)-1,2-dihydroisoquinoline-8-carbonitrile(6, 0.2 g, 0.793 mmol) in acetonitrile (2 mL),1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) or selectfluor (0.42 g, 1.190 mmol) and catalyticamount of acetic acid are added and the reaction mixture is stirred at60° C. for 8 h. After completion, the reaction mixture is quenched withwater and extracted with ethyl acetate. The organic layer is washed withbrine solution, dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure. The crude is purified by columnchromatography using silica gel (100-200 mesh) and 0-40% ethyl acetatein hexane as eluent. The desired fractions are concentrated underreduced pressure to afford4-fluoro-3-methyl-1-oxo-6-(trifluoromethyl)-1,2-dihydroisoquinoline-8-carbonitrile(7).

Example 3A.10

A bottle of 1,4-dioxane is sparged with argon gas for 10 min. Methyl2-bromo-6-chlorobenzoate (1, 257.7 mg, 1.0 mmol), SPhos (37.0 mg, 0.09mmol), palladium(II) acetate (6.7 mg, 0.03 mmol), potassium carbonate(276.9 mg, 2.0 mmol) and2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1a, 257.7 mg,1.0 mmol) are dissolved in 1,4-dioxane (2 mL) and water (0.20 mL) in anoven-dried screw cap vial equipped with a stir bar. The vial is sealedand the reaction mixture sparged with argon gas for 5 min. The reactionmixture is stirred vigorously at 100° C. for 13 h. The reaction mixtureis then cooled to room temperature and diluted with water (20 mL). Thesolids are filtered to afford a thick yellow semisolid that is taken upin dichloromethane (20 mL) and filtered again. The white solids thatremained are collected and dried, affording7-chlorophenanthridin-6(5H)-one (2).

Example 3A.11

To a stirred solution of 3,5-bis(trifluoromethyl)aniline (1, 10 g, 43.64mmol) and 402f (1a, 8.66 g, 52.37 mmol) in water (90 mL) is addedhydroxyl amine hydrochloride (10.91 g, 157.11 mmol), followed by sodiumsulphate (13.63 g, 96.01 mmol) at room temperature and the mixture isstirred at same temperature for 10 min. Concentrated hydrochloric acid(10.0 mL) is added slowly. The reaction mixture is heated to reflux for16 h and allowed to cool to room temperature. The solid precipitateformed is filtered and washed with diethyl ether and dried under vacuumto afford(E)-N-(3,5-bis(trifluoromethyl)phenyl)-2-(hydroxyimino)acetamide (2).

A solution of(E)-N-(3,5-bis(trifluoromethyl)phenyl)-2-(hydroxyimino)acetamide (2, 8.0g, 26.65 mmol) in concentrated sulfuric acid (60.0 mL) is heated to 85°C. and stirred for 4 h. After completion, the reaction is quenched withice cold water. Solid is obtained, filtered, washed with water and dryunder vacuum to afford 4,6-bis (trifluoromethyl) indoline-2,3-dione (3).

To a stirred solution of 4,6-bis (trifluoromethyl) indoline-2,3-dione(3, 6.5 g, 22.96 mmol) in 1 N sodium hydroxide solution (120.0 mL) isadded hydrogen peroxide solution (30% in water, 9.10 mL, 80.36 mmol)drop wise at 0° C. The reaction is allowed to warm up to roomtemperature and stirred for 4 h. After completion, the reaction mixtureis quenched with 1 N hydrochloric acid and extracted with ethyl acetate.The organic layer is washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated to dryness under reduced pressure toafford 2-amino-4,6-bis(trifluoromethyl)benzoic acid (4).

Example 3A.12

To a solution of7-chloro-6-fluoro-2-methyl-4-oxo-3,4-dihydroquinazoline-5-carbonitrile(5, 0.280 g, 1.17 mmol) in ethanol (3 mL), methylhydrazine (7, 0.33 mL,5.85 mmol) is added. This mixture is heated at 100° C. for 16 h. Thereaction mixture is cooled and the resulting precipitate is collected byfiltration and dried to afford1-amino-4-chloro-3,7-dimethyl-3,8-dihydro-9H-pyrazolo[4,3-f]quinazolin-9-one(6).

To a solution of1-amino-4-chloro-3,7-dimethyl-3,8-dihydro-9H-pyrazolo[4,3-f]quinazolin-9-one(6, 0.100 g, 0.37 mmol) in tetrahydrofuran (2 mL), tert-butyl nitrite(0.14 mL, 1.1 mmol) is added. This mixture is heated at 70° C. for 16 h.The reaction mixture is cooled, diluted with water, and extracted with10% methanol in dichloromethane. The organic layer is dried overanhydrous sodium sulfate, filtered, and concentrated. The crude productis purified by silica gel (100-200 mesh) column chromatography using0-70% ethyl acetate in hexanes as eluent to afford4-chloro-3,7-dimethyl-3,8-dihydro-9H-pyrazolo[4,3-f]quinazolin-9-one(7).

Example 3A.13

p-Toluenesulfonic acid monohydrate (74.7 mg, 0.39 mmol) is added to astirred solution of 5-benzyloxypentan-2-one (5, 3.02 g, 15.7 mmol) inmethanol (15 mL) and trimethyl orthoformate (3.44 mL, 31.4 mmol) at roomtemperature under a reflux condenser under argon. The resulting reactionmixture is heated at 50° C. under a reflux condenser under argon for 1.5h. After cooling to room temperature, sodium methoxide (25 wt. % inmethanol) (0.18 mL, 0.78 mmol) is added and then most of the solvent isremoved on a rotary evaporator. The residue is partitioned between ethylacetate and brine with a little 0.1 N NaOH in it. The organics arewashed with brine, dried over magnesium sulfate, filtered, concentratedon a rotary evaporator, and dried under high vacuum to afford crude(((4,4-dimethoxypentyl)oxy)methyl)benzene (6).

2-Bromo-6-(methylamino)-4-(trifluoromethyl)benzamide (4, 1.11 g, 3.7mmol), (((4,4-dimethoxypentyl)oxy)methyl)benzene (6, 1.33 g, 5.6 mmol),p-toluenesulfonic acid monohydrate (35.5 mg, 0.19 mmol) and toluene (20mL) are combined in a 100 mL round bottom flask with a stirbar, stirredvigorously, and heated at 100° C. under argon for 40 min. Most of thevolatiles are removed on a rotary evaporator. The residue is purifiedvia silica gel chromatography (10-80% ethyl acetate in hexanes) toafford2-(3-(benzyloxy)propyl)-5-bromo-1,2-dimethyl-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one(7).

2-(3-(benzyloxy)propyl)-5-bromo-1,2-dimethyl-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one(7, 1.64 g, 3.48 mmol), acetic anhydride (11.1 mL, 118 mmol), andpyridine (1.12 mL, 13.9 mmol) are combined in a sealable vessel with astirbar, sealed, stirred, and heated at 110° C. with a block heater for16 h. Most of the volatiles are removed on a rotary evaporator. Theresidue is taken up in ethyl acetate and purified via silica gelchromatography (30-90% ethyl acetate in hexanes) to afford2-(3-(benzyloxy)propyl)-5-bromo-1-methyl-7-(trifluoromethyl)quinolin-4(1H)-one(8) and3-(2-(benzyloxy)ethyl)-5-bromo-1,2-dimethyl-7-(trifluoromethyl)quinolin-4(1H)-one(9).

Example 3A.14

To a solution of4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzene-1,2-diamine (3,12.0 g, 43.7 mmol) in ethanol (120 mL) at 0° C. is added ethyl pyruvate(10.0 g, 87.5 mmol) and the reaction mixture is stirred for 3 h at roomtemperature. After completion, the reaction mixture is cooled to 0° C.,filtered and washed with diethyl ether which is dried under reducedpressure to afford3-methyl-7-(4-methylpiperazin-1-yl)-6-(trifluoromethyl)quinoxalin-2(1H)-one(4).

To a solution of3-methyl-7-(4-methylpiperazin-1-yl)-6-(trifluoromethyl)quinoxalin-2(1H)-one(4, 4.3 g, 13.1 mmol) is added phosphoryl chloride (43 mL) at roomtemperature. Then the reaction mixture is stirred for 6 h at 90° C.After completion, the reaction mixture is quenched with ice-cold water,adjusted the pH 8 with 1N aqueous hydrochloric acid solution andextracted with ethyl acetate, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to get the crude mass.The crude compound is purified by Combi flash (12 g, Redi Sep column)using 4% methanol in dichloromethane as eluent. The desired fractionsare concentrated under reduced pressure to afford2-chloro-3-methyl-7-(4-methylpiperazin-1-yl)-6-(trifluoromethyl)quinoxaline(5).

Example 3A.15

To4-benzyloxy-1-[2-fluoro-6-prop-1-ynyl-4-(trifluoromethyl)phenyl]butan-1-one(1, 50 .mg, 0.13200 mmol) in 1,4-Dioxane (1 mL) and water (0.01 mL,0.79000 mmol) is added dichloroplatinum (3.52 mg, 0.01320 mmol) and CO(29.6 mg, 1.06 mmol) is bubbled through the reaction mixture for 5 mins.The mixture is stirred at 25° C. for 30 min followed by heating to 100for 12 hr to afford2-(2-(benzyloxy)ethyl)-8-fluoro-3-methyl-6-(trifluoromethyl)naphthalen-1-ol(2) after workup.

Example 3A.16

A mixture of 2-amino-6-bromo-3-fluorobenzoic acid (2.00 g, 8.55 mmol)and urea (4.00 g, 66.60 mmol) is heated at 180° C. for 3 h, then cooledto 80° C. Water (7-10 mL) is added. The reaction is stirred at refluxfor 10 m. The resulting mixture is cooled to room temperature andfiltered. The dark brown solid is washed with water and ethyl ether, anddried under vacuum to afford5-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (2).

To a solution of 5-bromo-8-fluoroquinazoline-2,4(1H,3H)-dione (2, 445mg, 1.72 mmol) in phosphorus oxychloride (6.2 mL) is addedN,N-diisopropylethylamine (1.20 mL, 6.89 mmol) dropwise. The reaction isstirred at 120° C. overnight. The resulting mixture is cooled to roomtemperature and azeptroped with toluene. The crude is diluted with ethylacetate and washed with water. The combined organics are dried oversodium sulfate, decanted and concentrated. The crude is purified viacolumn chromatography (silica, ethyl acetate/hexanes=0-10%) to afford5-bromo-2,4-dichloro-8-fluoroquinazoline (3).

To a solution of 5-bromo-2,4-dichloro-8-fluoroquinazoline (3, 395 mg,1.33 mmol) in tetrahydrofuran (2 mL) is added 1 M sodium hydroxidesolution (6.70 mL, 6.70 mmol). The reaction is stirred at roomtemperature for 1 h 45 min. The resulting mixture is acidified to ˜pH 4with acetic acid. The precipitate is filtered, washed with ethyl etherand dried under vacuum to afford5-bromo-2-chloro-8-fluoroquinazolin-4(3H)-one (4).

To a solution of 5-bromo-2-chloro-8-fluoroquinazolin-4(3H)-one (4, 100mg, 0.36 mmol) in N,N-dimethylformamide (2 mL) is added1-(4-methoxyphenyl)-N-methylmethanamine (68 uL, 0.45 mmol). The reactionis microwaved at 120° C. for 10 m. The resulting mixture is cooled toroom temperature and sit for 90 min. The precipitate is filtered andwashed with ethyl ether. The filtrate is concentrated and trituratedwith ethyl acetate. The combined solids are dried under vacuum to afford5-bromo-8-fluoro-2-((4-methoxybenzyl)(methyl)amino)quinazolin-4(3H)-one(5).

Example 3A.17

To a solution of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (1, 25.0 g,132.9 mmol) in tetrahydrofuran (250 mL), N-iodosuccinimide (35.89 g,159.5 mmol) is added portion wise over a period of 10 min and thereaction mixture is allowed to stir at room temperature for 30 h. Aftercompletion, the reaction mixture is quenched with water and extractedwith ethyl acetate. The organic layer is washed with water, separated,dried over anhydrous sodium sulphate and concentrated under reducedpressure to afford 2,4-dichloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (2).

To a solution of 2,4-dichloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (2,30.0 g, 95.5 mmol) in methanol (600 mL), potassium carbonate (39.62 g,286.7 mmol) is added portion wise over a period of 10 min and thereaction mixture is allowed to stir at 80° C. for 24 h. Aftercompletion, the reaction mixture is concentrated, diluted with water andextracted with ethyl acetate. The organic layer is washed with water,separated, dried over anhydrous sodium sulphate and concentrated underreduced pressure to get crude. The crude is triturated with diethylether to afford 2-chloro-7-iodo-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine(3).

To a solution of 2-chloro-7-iodo-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine(3, 24.0 g, 77.54 mmol) in N,N-dimethylformamide (240 mL), zinc cyanide(9.11 g, 77.54 mmol), zinc acetate (14.22 g, 77.54 mmol) and zinc dust(2.02 g, 31.01 mmol) are added at room temperature. The reaction mixtureis degassed with argon for 15 min.[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) (5.67 g, 7.75 mmol)and palladium acetate (0.87 g, 3.87 mmol) are added and mixture isheated at 80° C. for 1 h. After completion, the reaction mass is dilutedwith ethyl acetate and washed with cold water. The organic layer isseparated, dried over anhydrous sodium sulphate, filtered andconcentrated to get crude. The crude is purified by columnchromatography over silica gel (100-200 mesh) using 0-50% ethyl acetatein hexanes as eluent. The desired fractions are concentrated in vacuo toafford 2-chloro-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile(4).

To a solution of2-chloro-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile (4, 10.0g, 47.9 mmol) in isopropanol (100 mL), aniline (5, 43.76 mL, 479.3 mmol)and p-toluene sulfonic acid monohydrate (10.93 g, 57.48 mmol) are added.The reaction mixture is allowed to stir at 80° C. for 16 h. Aftercompletion, the reaction mixture is quenched with water and extractedwith ethyl acetate. The organic layer is washed with water, brine, driedover anhydrous sodium sulphate and concentrated under reduced pressureto get crude. The crude is triturated with n-pentane, diethyl ether anddried under high vacuo to afford4-methoxy-2-(phenylamino)-5H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile(6).

Example 3B. Methods of Synthesizing the Right-Hand Side Example 3B.1

A solution of 4-bromo-1-chloro-2-fluorobenzene (1, 20.0 g, 95.69 mmol)in tetrahydrofuran (200 mL) is cooled at −78° C., then lithiumdi-isopropyl amide (2 M in tetrahydrofuran) (57.2 mL, 114.83 mmol) isadded dropwise to the mixture and reaction mixture is stirred at −78° C.for 1 h. Then, N,N-dimethylformamide (20.0 mL) is added drop wise for 15min at −78° C. and reaction mixture is stirred for 30 min. Aftercompletion reaction mixture is quenched with ammonium chloride solution,diluted with water, and extracted with diethyl ether. The organic layeris dried over anhydrous sodium sulphate, filtered and concentrated toget crude compound. Crude compound obtained is washed with pentane toafford 6-bromo-3-chloro-2-fluorobenzaldehyde (2).

To a solution of 6-bromo-3-chloro-2-fluorobenzaldehyde (2, 18.0 g, 75.94mmol), in acetonitrile (180.0 mL) and dimethylsulphoxide (48.0 mL),triethyl amine (31.96 mL, 227.84 mmol) is added at 0° C. followed byethyl 2-mercaptoacetate (2a, 18.2 g, 151.89 mmol) and continued stirringat 50° C. for 4 h. After completion, reaction mixture is diluted withwater and extracted with ethyl acetate, washed with 1 N hydrochloricacid, water and brine solution. Organic layer is dried over sodiumsulfate and concentrated to dryness under reduced pressure. Trituratedwith ethanol, filtered and dried to afford ethyl4-bromo-7-chlorobenzo[b]thiophene-2-carboxylate (3).

To a solution of ethyl 4-bromo-7-chlorobenzo[b]thiophene-2-carboxylate(3, 18.0 g, 56.42 mmol) and in tetrahydrofuran:water:methanol (90.0 mL:45 mL: 45 mL), lithium hydroxide (13.54 g, 564.26 mmol) is added, andthe reaction mixture is continued stirring for 2 h. After completion,reaction mixture is poured on chilled 1 N aqueous hydrochloric acid, andextracted with ethyl acetate, washed with water and brine solution.Organic layer is dried over anhydrous sodium sulfate and concentrated todryness under reduced pressure. Triturated with ether, filtered anddried to afford 4-bromo-7-chlorobenzo[b]thiophene-2-carboxylic acid (4).

To a solution of 4-bromo-7-chlorobenzo[b]thiophene-2-carboxylic acid (4,15.0 g, 51.90 mmol), in N,N-dimethyl acetamide (150.0 mL),1,8-diazabicyclo (5.4.0) undec-7-ene (39.55 g, 259.51 mmol) is added andmixture is heated at 180° C. for 4 h. After completion, reaction mixtureis cooled to room temperature diluted with water and acidified by 1 Nhydrochloric acid and extracted with ethyl acetate, washed with, waterand brine solution. Organic layer is dried over anhydrous sodium sulfateand concentrated to dryness under reduced pressure to afford4-bromo-7-chlorobenzo[b]thiophene (5).

To a solution of 4-bromo-7-chlorobenzo[b]thiophene (5, 4.00 g, 16.19mmol) in dichloromethane (100.0 mL), dichloro(methoxy)methane (5a, 4.59g, 24.29 mmol) is added at 0° C. followed by titanium tetrachloride(2.79 g, 24.29 mmol) at same temperature and the reaction mixture iscontinued stirring for 16 h at room temperature. After completion,reaction mixture is quenched with 1 N aqueous hydrochloric acid andcontinued stirring for 2 h, diluted with water and extracted withdichloromethane, washed with water and brine solution. Organic layer isdried over anhydrous sodium sulfate and concentrated to dryness underreduced pressure. The crude product is purified by flash chromatographyusing silica (100-200 mesh) using 0-10% ethyl acetate in hexanes aseluent. The desired fractions are concentrated under reduced pressure toafford 4-bromo-7-chlorobenzo[b]thiophene-3-carbaldehyde (6).

To a solution of 4-bromo-7-chlorobenzo[b]thiophene-3-carbaldehyde (6,2.50 g, 9.12 mmol) in 1,4-dioxane (24.0 mL) and water (8.0 mL), (3:1ratio) is added sodium chlorite (1.24 g, 13.68 mmol), followed bysulfamic acid (5.30 g, 54.74 mmol) at room temperature and the mixtureis continued stirring for 16 h. After completion, reaction mixture isconcentrated under reduced pressure; residue is acidified to pH-2 by 2 Nhydrochloric acid and extracted with ethyl acetate, washed with waterand brine solution. Organic layer is dried over anhydrous sodium sulfateand concentrated to dryness under reduced pressure. The residue istriturated with n-pentane, filtered and dried to afford4-bromo-7-chlorobenzo[b]thiophene-3-carboxylic acid (7).

To a solution of 4-bromo-7-chlorobenzo[b]thiophene-3-carboxylic acid (7,1.40 g, 4.81 mmol) in t-butanol (15.0 mL), di-tert-butyl dicarbonate(2.0 g, 9.62 mmol) followed by dimethylaminopyridine (0.586 g, 4.81mmol) is added at room temperature. The solution is heated at 90° C. andcontinued stirring for 16 h. After completion, reaction mixture isconcentrated under reduced pressure; diluted with water and extractedwith ethyl acetate, washed with water and brine solution. Organic layeris dried over sodium sulfate and concentrated to dryness under reducedpressure. The crude is purified by flash chromatography using silica(100-200 mesh) by eluting with gradient of 5-10% ethyl acetate inhexanes. The desired fractions are concentrated under reduced pressureto afford tert-butyl 4-bromo-7-chlorobenzo[b]thiophene-3-carboxylate(8).

A solution of tert-butyl 4-bromo-7-chlorobenzo[b]thiophene-3-carboxylate(8, 1.10 g, 3.17 mmol) and tributyl(vinyl)stannane (1.20 g, 3.80 mmol)in N,N-dimethylformamide (11 mL) is degassed using argon for 15 min.Bis(triphenylphosphine)palladium dichloride (0.222 g, 0.3170 mmol) isadded to the reaction mixture and heated at 90° C. for 2 h. The reactionmixture is cooled to room temperature, diluted with ethyl acetate andwater. The organic layer is separated, washed with brine, dried overanhydrous sodium sulphate, filtered and concentrated under reducedpressure to get the crude. The crude is purified by columnchromatography using silica (100-200 mesh) and 2.0-5.0% ethyl acetate inhexanes as eluent. The desired fractions are concentrated under reducedpressure to afford tert-butyl7-chloro-4-vinylbenzo[b]thiophene-3-carboxylate (9).

A solution of tert-butyl 7-chloro-4-vinylbenzo[b]thiophene-3-carboxylate(9, 0.6 g, (2.04 mmol) in acetone (10 mL) and water (2 mL) is cooled to0° C. and osmium tetraoxide (4% solution in water)(1.3 mL, 0.2040 mmol)followed by sodium periodate (1.3 g, 6.12 mmol) is added. The mixture isstirred at room temperature for 1 h. After completion, the reactionmixture is filtered and filtrate is concentrated under reduced pressureto get the crude product. The crude is purified by pentane wash toafford tert-butyl 7-chloro-4-formylbenzo[b]thiophene-3-carboxylate (10).

To a stirred solution of tert-butyl7-chloro-4-formylbenzo[b]thiophene-3-carboxylate (10, 0.550 g, 1.85mmol) in dichloromethane (10 mL), diethylaminosulfur trifluoride (0.503g, 2.77 mmol) is added at 0° C. The reaction is allowed to warm at roomtemperature and stirred for 4 h. After completion, reaction mixture isconcentrated under reduced pressure to get crude. The crude is purifiedby column chromatography using silica (100-200 mesh) and 5.0-10.0% ethylacetate in hexanes as eluent. The desired fractions are concentratedunder reduced pressure to afford tert-butyl7-chloro-4-(difluoromethyl)benzo[b]thiophene-3-carboxylate (11).

Example 3B.2

A solution of 3′-bromo-5-chloro-[1,1′-biphenyl]-2-ol (3, 0.5 g, 1.7mmol), diisopropyl phosphonate (4, 0.585 g, 3.5 mmol), and triethylamine (0.533 g, 5.2 mmol) in isopropyl alcohol is degassed with argonfor 10 min followed by the addition of bis(diphenylphosphino)ferrocene-palladium(II)dichloride.dichloromethane complex The reactionmixture is stirred at 100° C. for 16 h. After completion, the volatilesare removed under reduced pressure. Crude is purified by flash columnchromatography using 30% ethyl acetate hexanes to afford diisopropyl(5′-chloro-2′-hydroxy-[1,1′-biphenyl]-3-yl)phosphonate (5).

Example 3B.3

To a solution of 7-bromo-5-methylthieno[3,2-b]pyridine-3-carboxamide (3,1.50 g, 5.55 mmol) in N,N-dimethylformamide (20 mL), sodium hydride isadded at 0° C. and stirred for 10 min. Then, dimethylcarbamic chloride(3a, 0.71 g, 6.66 mmol) is added and the mixture is stirred at roomtemperature for 2 h. After completion, the reaction mixture is dilutedwith ethyl acetate, washed with cold water and brine, dried overanhydrous sodium sulphate, filtered and concentrated. The crude productis triturated with diethyl ether and pentane and dried to afford7-bromo-N-(dimethylcarbamoyl)-5-methylthieno[3,2-b]pyridine-3-carboxamide(4).

Example 3B.4

Methyl 2-hydroxythieno[3,2-b]pyridine-3-carboxylate (1, 748 mg, 3.6mmol) is dissolved in N,N-dimethylformamide (20 mL) in an oven driedscrew cap vial equipped with a stir bar. Potassium carbonate (210 mg,1.52 mmol) is added, followed by the dropwise addition of1-(chloromethyl)-4-methoxybenzene (1a, 0.42 mL, 4.2 mmol). The vial issealed and heated to 75° C. After 22 h additional 4-methoxybenzylchloride (0.42 mL, 4.2 mmol) and potassium carbonate (946.2 mg, 6.8mmol) are added and the reaction mixture continued to stir at 75° C.After 3 h the reaction mixture is cooled to room temperature and dilutedwith ethyl acetate and water. The layers are separated and the aqueousphase is extracted with ethyl acetate twice. The combined organicmaterial is washed with brine, dried over magnesium sulfate, filtered,and solvent removed in vacuo to afford a dark brown oil. Purificationvia silica gel chromatography, eluting with hexanes and ethyl acetateafforded methyl2-((4-methoxybenzyl)oxy)thieno[3,2-b]pyridine-3-carboxylate (2).

A bottle of tetrahydrofuran is sparged with argon gas for 1 h. An ovendried microwave vial equipped with a stir bar is charged withbis(pinacolato)diboron (308.4 mg, 1.21 mmol), methyl2-((4-methoxybenzyl)oxy)thieno[3,2-b]pyridine-3-carboxylate (2, 381 mg,1.16 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (2a, 21.8 mg, 0.093mmol), and (1Z,5Z)-cycloocta-1,5-diene; methoxyiridium (30.6 mg, 0.046mmol). Tetrahydrofuran (2.3 mL) is added, the vial is sealed and placedunder an atmosphere of argon before being stirred in an oil bath at 80°C. After 16 h the reaction mixture is cooled to room temperature andsolvent removed in vacuo. The crude residue is used without furtherpurification for the subsequent reaction. Methyl2-((4-methoxybenzyl)oxy)-7-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine-3-carboxylate(3).

Example 3B.5

To a solution of 3-(benzylthio)-7-chloro-5-methylthieno[3,2-b]pyridine(1, 0.7 g, 2.3 mmol) in a mixture of acetonitrile, acetic acid and water(40:2:1) (10.0 mL) at 0° C.1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (1a, 0.9 g, 4.60 mmol)at 0° C. and the mixture is stirred for 1 h. Ammonium hydroxide (35% inwater, 6.0 mL) is added is added to the reaction mixture at 0° C. andstirring is continued for 2 h. After completion, the reaction mixture isdiluted with water and extracted with ethyl acetate. The organic layeris washed with water and saturated brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The crude product is washed withn-pentanes to afford7-chloro-5-methylthieno[3,2-b]pyridine-3-sulfonamide (2).

To a solution of methyl7-chloro-5-methylthieno[3,2-b]pyridine-3-sulfonamide (2, 0.50 g, 1.9mmol) in acetic anhydride (6.0 mL) is added zinc chloride (0.08 g, 0.57mmol) at room temperature and the mixture is heated and stirred for 16 hat 75° C. After completion, the reaction mixture is diluted with waterand extracted with ethyl acetate. The organic layer is washed withwater, saturated brine, dried over anhydrous sodium sulfate, filteredand concentrated. The crude product is purified by washing with diethylether and n-pentanes to affordN-((7-chloro-5-methylthieno[3,2-b]pyridin-3-yl)sulfonyl)acetamide (3).

Example 3B.6

A solution of5-(1-((4-bromothiophen-3-yl)amino)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione(1, 0.250 g, 0.722 mmol) in N-methyl pyrrolidone (2 mL) is heated inmicrowave at 200° C. for 30 min. After completion, the reaction mixtureis diluted with dichloromethane and then silica gel is added. Thesolvent is then evaporated and the free flow silica gel is then loadedon the Isco column and purified via silica gel chromatography elutingwith methanol/ethylacetate. The desired fractions are concentrated underreduced pressure to afford 3-bromo-5-methylthieno[3,2-b]pyridin-7-ol(2).

To a solution of 3-bromo-5-methylthieno[3,2-b]pyridin-7-ol (2, 177 mg,0.725 mmol), phenylmethanethiol (2a, 0.361 g, 2.91 mmol) andN,N-diisopropylethylamine (0.379 mL, 2.15 mmol) in monoglyme (4 mL) isadded premixed solution of tris(dibenzylideneacetone)dipalladium(0) (132mg, 0.145 mmol) and(R)-1-[(S_(P))-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(80 mg, 0.145 mmol) in monoglyme (1 mL) at room temperature. Thereaction mixture is purged with argon gas for 5 min, and the mixture isheated at 110° C. for 15 h. After completion, the reaction mixture isdiluted with dichloromethane and then silica gel is added. The solventis then evaporated and the free flow silica gel is then loaded on theIsco column and purified via silica gel chromatography eluting withEthylacetate/hexanes. The desired fractions are concentrated underreduced pressure to afford3-(benzylthio)-5-methylthieno[3,2-b]pyridin-7-ol (3).

To a solution of 3-(benzylthio)-5-methylthieno[3,2-b]pyridin-7-ol (3,0.100 g, 0.347 mmol) in 1,2-dichloroethane (3.0 mL), phosphoryltrichloride (0.1 mL, 1.04 mmol) and catalytic amount ofN,N-dimethylformamide (0.050 mL) are added at room temperature. Thereaction mixture is heated at 90° C. for 2 h. After completion, thereaction mixture is diluted with dichloromethane and then silica gel isadded. The solvent is then evaporated and the free flow silica gel isthen loaded on the Isco column and purified via silica gelchromatography eluting with methanol/dichloromethane to afford3-(benzylthio)-7-chloro-5-methylthieno[3,2-b]pyridine (4).

A solution of 3-(benzylthio)-7-chloro-5-methylthieno[3,2-b]pyridine (4,50 mg, 0.163 mmol) and 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione(4a, 64 mg, 0.329 mmol) in mixture of acetonitrile (3 mL)/water (2mL)/acetic acid (0.4 mL) is stirred at room temperature for 1 h. To thismixture is then added hydroxyl(trimethylstannane) (295 mg, 1.63 mmol)and then stirred for 15 h at 50° C. The reaction mixture is thenconcentrated to afford crude7-chloro-5-methylthieno[3,2-b]pyridine-3-sulfonic acid (5).

Example 3B.7

To a solution of methyl7-bromo-5-methylthieno[3,2-b]pyridine-3-carboxylate (1, 3.00 g, 10.4mmol) in dichloromethane (30.0 mL) at −78° C., diisobutylaluminiumhydride (10.40 mL, 15.7 mmol) is added. The reaction mixture is stirredthis temperature for 3 h. After this time, the reaction mixture isdiluted with water and extracted with dichloromethane. The organic layeris washed with water and then brine, dried over anhydrous sodiumsulfate, and concentrated to dryness under reduced pressure to afford(7-bromo-5-methylthieno[3,2-b]pyridin-3-yl)methanol (2).

To a solution of (7-bromo-5-methylthieno[3,2-b]pyridin-3-yl)methanol (2,1.70 g, 3.87 mmol) in dichloromethane (20.0 mL) at 0° C.,1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (3.28 g,7.75 mmol) is added. The reaction mixture is stirred at room temperaturefor 3 h. After this time, the reaction mixture is filtered with Celiteand washed with dichloromethane. The filtrate is concentrated to drynessunder reduced pressure to obtain the crude product. This is purified bysilica gel (100-200 mesh) column chromatography using 30-50% ethylacetate in hexanes as eluent. The desired fractions are concentratedunder reduced pressure to afford7-bromo-5-methylthieno[3,2-b]pyridine-3-carbaldehyde (3).

To a solution of 7-bromo-5-methylthieno[3,2-b]pyridine-3-carbaldehyde(3, 0.50 g, 1.95 mmol) in dichloromethane (5.0 mL) at 0° C.,trifluoromethyltrimethylsilane (0.416 g, 2.92 mmol) and cesium carbonate(3.17 g 9.75 mmol) is added. The reaction mixture is stirred at roomtemperature for 1 h. Then, the reaction mixture is diluted with waterand extracted with dichloromethane. The organic layer is washed withwater and then brine solution, dried over anhydrous sodium sulfate, andconcentrated to dryness under reduced pressure to afford7-bromo-5-methyl-3-(2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)thieno[3,2-b]pyridine(4).

Example 3B.8

To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (1, 20 g, 145.0mmol) in acetonitrile (80 mL) are added sodium iodide (24 g, 160.0 mmol)and chloramine tetrahydrate (45 g, 160.0 mmol) and stirred at roomtemperature for 16 h. The reaction mixture is diluted with water andextracted with ethyl acetate. The organic layer is washed with water andsaturated brine, dried over anhydrous sodium sulphate, filtered andconcentrated. The crude product is purified by column chromatographyusing silica gel (100-200 mesh) and 10% ethyl acetate in hexanes aseluent. The desired fractions are concentrated under reduced pressure toafford 2-fluoro-4-hydroxy-5-iodobenzonitrile (2).

To a solution of 2-fluoro-4-hydroxy-5-iodobenzonitrile (2, 7.0 g, 26.6mmol) in 1,4-dioxane (70 mL), sodium acetate (4.36 g, 53.23 mmol) andbis pinacolato diboron (20.26 g, 79.8 mmol) are added at roomtemperature and the mixture is degassed with argon for 10 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethanecomplex (1.9 g, 2.66 mmol), is added to the reaction mixture anddegassed for another 15 min. The reaction mixture is heated at 75° C.for 16 h. After completion, the reaction mass is diluted with water andextracted with ethyl acetate. The organic layer is washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated todryness under reduced pressure. The crude product is purified byCombiflash (12 g, RediSep column) using 20% ethyl acetate in hexanes aseluent. The desired fractions are concentrated under reduced pressure toafford2-fluoro-4-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(3).

Example 3B.9

A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1a, 1.048 g, 7.27mmol) and 1,1,1-triethoxyethane (10.0 mL) is stirred and heated at 90°C. for 2 h in a closed vessel. Methyl 2-aminobenzoate (1, 1 g, 6.62mmol) is added portion wise at 90° C. under argon atmosphere andcontinued heating at 90° C. for 6 h. After completion, the reaction massis cooled to room temperature, added water and extracted with ethylacetate. The organic layer is dried over anhydrous sodium sulfate,filtered and concentrated under vacuo to get crude. The crude methyl2-((1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethyl)amino)benzoate(2).

A solution of methyl2-((1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)ethyl)amino)benzoate(2, 0.900 g, 2.82 mmol) in N-methyl pyrrolidone (1 mL) is heated inmicrowave at 200° C. for 30 min. After completion, the reaction mixtureis diluted with dichloromethane and then silica gel is added. Thesolvent is then evaporated and the free flow silica gel is then loadedon the Isco column and purified via silica gel chromatography elutingwith methanol/ethylacetate. The desired fractions are concentrated underreduced pressure to afford methyl4-hydroxy-2-methylquinoline-8-carboxylate (3).

Example 3B.10

A solution of methyl 5-formylthiophene-3-carboxylate (1, 2.00 g, 11.7mmol) and 4-methylbenzenesulfonohydrazide (2.19 g, 11.7 mmol) in1,4-dioxane (20 mL) is heated at 90° C. for 16 h. The reaction mixtureis cooled at room temperature, concentrated under reduced pressure toget the crude. The crude is washed with diethyl ether and dried undervacuum to afford methyl(Z)-5-((2-tosylhydrazineylidene)methyl)thiophene-3-carboxylate (2).

To a solution of methyl(Z)-5-((2-tosylhydrazineylidene)methyl)thiophene-3-carboxylate (2, 0.50g, 1.47 mmol), (5-chloro-2-hydroxyphenyl)boronic acid (2a, 0.307 g, 1.77mmol) and potassium carbonate (0.40 g, 2.94 mmol) in 1,4-dioxane:water(4:1, 5 mL) is added and reaction mixture is stirred at 90° C. for 16 h.After completion, the reaction mixture is diluted with water andextracted with ethyl acetate. The organic layer is dried over anhydroussodium sulfate, filtered and concentrated to dryness under reducedpressure to get crude. The crude is purified by flash columnchromatography using silica (100-200 mesh) and 10-20% ethyl acetate inhexanes as eluent to afford methyl5-(5-chloro-2-hydroxybenzyl)thiophene-3-carboxylate (3).

Example 3B.11

To a cooled solution of tert-butyl5′-chloro-2′-hydroxy-[1,1′-biphenyl]-3-carboxylate (1, 2.65 g, 8.7mmol), but-3-yn-1-ol (2, 0.66 mL, 8.7 mmol) and triphenylphosphine (2.28g, 8.7 mmol) in tetrahydrofuran (14 mL) at 5° C. is added diisopropylazodicarboxylate (1.71 mL, 8.7 mmol) via syringe over ca. 2 min. This iswarmed to room temperature after 15 min and stirred for an additional 18h. The solvent is removed in vacuo and residue purified via automatedflash chromatography, eluting with hexanes and ethyl acetate to affordtert-butyl 2′-(but-3-yn-1-yloxy)-5′-chloro-[1,1′-biphenyl]-3-carboxylate(3).

A flame-dried round bottom flask is charged with ethyl2,2,2-trifluoroacetate (4, 0.26 mL, 2.18 mmol) and tetrahydrofuran (13mL). It is cooled to −78° C. and boron trifluoride diethyl etherate(0.29 mL, 2.32 mmol) is added dropwise. After 50 min tert-butyl2′-(but-3-yn-1-yloxy)-5′-chloro-[1,1′-biphenyl]-3-carboxylate (3, 460mg, 1.29 mmol) is added slowly followed by slow addition ofn-butyllithium solution (2.5 M in hexanes, 0.62 mL, 1.55 mmol). After 1h the reaction is quenched at −78° C. with the slow addition ofsaturated aqueous ammonium chloride solution. The solution is warmed toroom temperature and ethyl acetate is added. The layers are separated,and the aqueous phase is extracted with ethyl acetate twice. Thecombined organic material is washed with brine, dried over magnesiumsulfate, filtered, and concentrated. Purification via automated flashchromatography, eluting with hexanes and ethyl acetate, affordedtert-butyl5′-chloro-2′-((6,6,6-trifluoro-5-oxohex-3-yn-1-yl)oxy)-[1,1′-biphenyl]-3-carboxylate(5)

Example 3C. General Coupling Methods Example 3C.1

Sodium methoxide (25 wt. % in methanol) (3.16 mL, 13.8 mmol) is added toa stirred solution of 3-chloro-2,6-difluoro-pyridine (2a, 2.01 g, 13.4mmol) in Methanol (5 mL) at 0° C. The cold bath is removed and theresulting cloudy mixture is stirred at room temperature under argon for35 min. The reaction mixture is poured into water (100 mL). Solids arecollected by vacuum filtration, washed thoroughly with water, and airdried using vacuum suction for 30 min. The solids are dried under highvacuum to afford 3-chloro-6-fluoro-2-methoxypyridine (2b).

Potassium carbonate (1.82 g, 13.2 mmol) is added to a stirred solutionof2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(1, 835 mg, 3.30 mmol) and 1,2-dibromoethane (2.84 mL, 33.0 mmol) in DMA(15 mL) at room temperature under argon. The resulting mixture is heatedat 60° C. under argon for 3 h. Water (0.59 mL, 33.0 mmol) is added. Theresulting mixture is heated at 60° C. under argon for 1 h 15 min. Aftercooling to room temperature the reaction mixture is partitioned betweenethyl acetate and water. The organics are washed three times with brine,dried over magnesium sulfate, filtered, concentrated on a rotaryevaporator, and purified via silica gel chromatography (20-90% ethylacetate in hexanes) to afford3-(2-hydroxyethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(2).

3-(2-Hydroxyethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(2, 390 mg, 1.31 mmol) is dissolved in DMF (4 mL) with stirring underargon. THF (6 mL) is added and the resulting solution is cooled to −78°C. Sodium hydride (34.6 mg, 1.44 mmol) is added and the resulting cloudymixture is stirred at −78° C. under argon for 10 min.3-Chloro-6-fluoro-2-methoxypyridine (2b, 254 mg, 1.57 mmol) is added andthe cold bath is removed. The resulting mixture is stirred at roomtemperature under argon for 20 min and then heated at 50° C. under areflux condenser under argon for 2.5 h. After cooling to roomtemperature the resulting mixture is partitioned between ethyl acetateand a mixture of brine and saturated aqueous ammonium chloride. Theorganics are washed twice more with brine, concentrated on a rotaryevaporator with silica gel, and purified via silica gel chromatography(0-100% ethyl acetate in hexanes) to afford impure3-(2-((5-chloro-6-methoxypyridin-2-yl)oxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(3).

Example 3C.2

To a solution of tert-butyl7-(5-chloro-2-hydroxyphenyl)thieno[3,2-b]pyridine-3-carboxylate (3a, 2.0g, 5.5 mmol) in tetrahydrofuran (15 mL), sodium hydride (0.276 g, 6.9mmol) is added at 0° C. and the mixture is stirred for 0.5 h.6-Chloro-3-(2-chloroethyl)-2-methyl-8-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(3, 1.5 g, 4.6 mmol) in tetrahydrofuran is added to the reaction mixtureand stirred for 16 h. After completion, the reaction mixture is pouredinto crushed ice and extracted with ethyl acetate. Organic layer isdried over anhydrous sodium sulfate and concentrated to dryness underreduced pressure. The crude compound obtained is purified through columnchromatography using 0-50% ethyl acetate in hexanes as eluent; thefractions containing desired product is distilled off under reducedpressure to afford tert-butyl7-(5-chloro-2-(2-(6-chloro-2-methyl-4-oxo-8-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-3-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(4).

Example 3C.3

To a mixture of5-bromo-8-fluoro-2-((4-methoxybenzyl)(methyl)amino)quinazolin-4(3H)-one(5, 95 mg, 0.23 mmol), tert-butyl2′-(2-bromoethoxy)-5′-chloro-[1,1′-biphenyl]-3-carboxylate (5a, 99 mg,0.24 mmol), nickel(II) iodide hydrate (30 mg, 0.08 mmol), sodium iodide(17 mg, 0.12 mmol), p-tolunitrile (11 mg, 0.09 mmol),4,4′-dimethoxy-2,2′-bipyridine (20 mg, 0.09 mmol) in freshly spargedN,N-dimethylacetamide (1.2 mL) are added chlorotrimethylsilane (1 drop),pyridine (1 drop) and manganese (25 mg, 0.46 mmol). The reaction isstirred at 80° C. overnight. The resulting mixture is cooled to roomtemperature and filtered through a pad of Celite. The filtrate isextracted with ethyl acetate and water. The combined organics are driedover sodium sulfate, decanted and concentrated. The crude is purifiedvia column chromatography (silica, ethyl acetate/hexanes=0-40%) toafford5′-chloro-2′-(2-(8-fluoro-2-((4-methoxybenzyl)(methyl)amino)-4-oxo-3,4-dihydroquinazolin-5-yl)ethoxy)-[1,1′-biphenyl]-3-carboxylicacid (6).

Example 3C.4

6-Amino-2-(phenylamino)pyrimidin-4-ol (6, 114 mg, 0.45 mmol) isdissolved in dimethylsulfoxide (1.1 mL) and tert-butyl5′-chloro-2′-((6,6,6-trifluoro-5-oxohex-3-yn-1-yl)oxy)-[1,1′-biphenyl]-3-carboxylate(5, 203 mg, 0.45 mmol) is added in 1 portion. The neon solution isstirred at room temperature for 19 h. The reaction mixture is dilutedwith water and filtered. The solid is dried in a vacuum oven for 2 h toafford tert-butyl5′-chloro-2′-(2-(4-oxo-2-(phenylamino)-7-(trifle.oromethyl)-3,4-dihydropyrido[2,3-d]pyrimidin-5-yl)ethoxy)-[1,1′-biphenyl]-3-carboxylate(7)

Example 3D. Post Coupling Modification Methods Example 3D.1

Methylmagnesium bromide (3 M in diethyl ether) (0.051 mL, 0.152 mmol) isadded to a stirred solution of methyl7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylate(1, 30.3 mg, 0.051 mmol) in THF (2.5 mL) at −78° C. under argon. Thereaction mixture quickly became dark yellow colored. After 20 min thereaction mixture is quenched with saturated aqueous ammonium chloride(0.5 mL), diluted with water (0.5 mL), and partitioned between ethylacetate and brine. The organics are dried over magnesium sulfate,filtered, concentrated on a rotary evaporator, and dried under highvacuum at 40° C. for 45 min to afford an orange residue. This isdissolved in THF (2.5 mL) with stirring and cooled to −78° C. underargon. Methylmagnesium bromide (3 M in diethyl ether) (0.051 mL, 0.152mmol) is added and the reaction mixture is stirred at −78° C. underargon for 20 min. The reaction mixture is quenched with saturatedaqueous ammonium chloride (0.5 mL), diluted with water (0.5 mL), andpartitioned between ethyl acetate and brine. The organics are dried overmagnesium sulfate, filtered, concentrated on a rotary evaporator, andpurified via preparatory HPLC (15-57% acetonitrile in water with 0.1%TFA). Fractions containing desired product are combined and neutralizedwith saturated aqueous sodium bicarbonate. The acetonitrile is removedon a rotary evaporator. The residual aqueous phase is extracted threetimes with dichloromethane. The combined organics are dried over sodiumsulfate, filtered, and concentrated on a rotary evaporator. The residueis taken up in acetonitrile and water and lyophilized to dryness toafford3-(2-(4-chloro-2-(3-(2-hydroxypropan-2-yl)thieno[3,2-b]pyridin-7-yl)phenoxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(Cpd. No. 352F).

Example 3D.2

To a solution7-(5-chloro-2-(2-(5-cyano-6-(difluoromethyl)-8-fluoro-2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (8, 0.10 g, 0.171 mmol) in N,N-dimethylformamide (2.0 mL),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (0.098 g, 0.256 mmol) is added and mixtureis stirred at room temperature for 15 min. The reaction mixture iscooled to 0° C., N,N-diisopropylethylamine (0.12 mL, 0.684 mmol) andO-methylhydroxylamine hydrochloride (8a, 0.017 g, 0.205 mmol) are addedand the mixture is stirred at room temperature for 1.5 h. Aftercompletion, the reaction mixture is diluted with ethyl acetate andwashed with cold water and brine solution, dried over anhydrous sodiumsulphate and concentrated under reduced pressure. The crude is purifiedby prep-HPLC to afford7-(5-chloro-2-(2-(5-cyano-6-(difluoromethyl)-8-fluoro-2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy)phenyl)-N-methoxythieno[3,2-b]pyridine-3-carboxamide(Cpd. No. 303F).

Example 3D.3

N,N-diisopropylethylamine (0.028 mL, 0.163 mmol) is added to a stirredmixture of7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylicacid (1, 32.5 mg, 0.054 mmol) and HATU (22.7 mg, 0.060 mmol) in DMF (0.3mL) at room temperature under argon. All solids dissolved within 5 minand then shortly thereafter a lot of solids precipitated. After 20 minglycine (6.1 mg, 0.081 mmol) is added followed by more DMF (0.2 mL). Theresulting mixture is sealed and stirred vigorously at room temperaturefor 20 min. More glycine (18.0 mg, 0.240 mmol) is added. The resultingmixture is sealed, stirred vigorously, and heated at 40° C. with aheating block for 14 h. The reaction mixture is diluted with methanol,filtered, and purified via preparatory HPLC (20-70% acetonitrile inwater with 0.1% TFA). Fractions containing the desired product arecombined and lyophilized to dryness to afford(7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carbonyl)glycine(Cpd. No. 398F).

Example 3D.4

1-Methylpiperazine (0.05 mL, 0.73 mmol) and methyl7-(5-chloro-2-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-3-((4-methoxybenzyl)oxy)thieno[3,2-b]pyridine-2-carboxylate(4, 82 mg, 0.11 mmol) are dissolved in N-methyl pyrrolidinone (1.8 mL)in a screw capped vial equipped with a stir bar. The vial is sealed andheated in a heating block at 145° C. for 4.5 h. The reaction mixture iscooled to room temperature. The reaction mixture is diluted with ethylacetate and filtered through Celite and volatile solvent removed invacuo. The residual material is diluted with dimethylsulfoxide andpurified via RP-HPLC to afford3-(2-(4-chloro-2-(3-hydroxythieno[3,2-b]pyridin-7-yl)phenoxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(Cpd. No. 663F).

Example 3D.5

To a solution of methyl2′-(2-(6-cyano-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-5′-formyl-[1,1′-biphenyl]-3-carboxylate(7, 0.10 g, 0.22 mmol) in dichloromethane (8 mL), diethylaminosulfurtrifluoride (0.052 g, 0.33 mmol) is added at 0° C. The reaction mixtureis stirred at room temperature for 16 h. After completion, the reactionmixture is quenched with 10% aqueous sodium hydroxide solution at 0° C.to pH˜7 and extracted with dichloromethane (50 mL). The organic layer iswashed with water (50 mL), brine (20 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to get crude. The crudeis purified by combiflash column (4 g, Redisep) using 10-50% ethylacetate in hexanes to afford methyl2′-(2-(6-cyano-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)ethoxy)-5′-(difluoromethyl)-[1,1′-biphenyl]-3-carboxylate(8).

Example 3D.6

N-bromosuccinimide (39.2 mg, 0.22 mmol) is added to a stirred solutionof3-(2-((5-chloro-6-methoxypyridin-2-yl)oxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(3, 92 mg, 0.21 mmol) in DMF (1 mL) at room temperature. The resultingclear yellow reaction mixture is capped and stirred at room temperaturefor 3.5 h. More N-bromosuccinimide (19.0 mg, 0.11 mmol) is added and thereaction mixture is capped and stirred at room temperature for 2 h. Thereaction mixture is diluted with ethyl acetate and washed three timeswith brine. The organics are dried over magnesium sulfate, filtered,concentrated on a rotary evaporator, and purified via silica gelchromatography (0-100% ethyl acetate in hexanes) to afford3-(2-((3-bromo-5-chloro-6-methoxypyridin-2-yl)oxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(4).

3-(2-((3-Bromo-5-chloro-6-methoxypyridin-2-yl)oxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(4, 76.3 mg, 0.147 mmol), potassium acetate (43.4 mg, 0.44 mmol),bis(pinacolato)diboron (44.9 mg, 0.177 mmol), PdCl₂(dppf).CH₂Cl₂ (12 mg,0.015 mmol), and 1,4-dioxane (0.5 mL) are combined in a 1 dram vial witha stirbar and sparged with argon gas for 1 min. The resulting mixture issealed, stirred vigorously, and heated at 90° C. with a heating blockfor 3 h. The reaction mixture is loaded directly onto a silica gelloading column and purified via silica gel chromatography (0-80% ethylacetate in hexanes) to afford impure3-(2-((5-chloro-6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(5)

Example 3D.7

To a solution of3-(2-((3-chloropyridazin-4-yl)oxy)ethyl)-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(2d, 20.0 mg, 0.049 mmol), methyl(3-(methoxycarbonyl)thieno[3,2-b]pyridin-7-yl)boronic acid (2, 15.58 mg,0.049 mmol), Potassium Carbonate (0.15 mL, 0.150 mmol) in 1,4-dioxane(1.5 mL) is added tetrakis(triphenylphosphine)palladium(0) (5.64 mg,0.0049 mmol) at room temperature and the mixture is degassed by bubblingargon through it for 5 min. The reaction mixture is heated to 90° C. for16 h. After completion of the reaction, the reaction is diluted withwater and extracted with ethyl acetate. The organic layer is washed withwater and saturated brine solution, dried over anhydrous sodiumsulphate, filtered, and concentrated to dryness under reduced pressure.The crude product is purified by Combiflash (12 g, RediSep column) using1-5% methanol in dichloromethane as eluent to afford methyl7-(4-(2-(5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)pyridazin-3-yl)thieno[3,2-b]pyridine-3-carboxylate(3).

Example 3D.8

A flame-dried vial is charged with tert-butyl7-(2-(2-(5-bromo-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(2, 106 mg, 0.150 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (10.8mg, 0.0457 mmol), copper(I) iodide (6.2 mg, 0.033 mmol), and cesiumcarbonate (94 mg, 0.290 mmol). The vial is evacuated and backfilled withargon twice. Toluene (1.4 mL) and (4-methoxyphenyl)methanol (29 uL, 33mg, 0.24 mmol) are added, and the mixture is degassed for 5 min, thenstirred at 110° C. After 4 h, the mixture is allowed to cool down toroom temperature and stir an additional 14 h, then diluted with EtOAc,then washed with water. The aq. phase is extracted (3× EtOAc), and thecombined organic phases are dried (Na₂SO₄), filtered, and concentrated.Purification by column chromatography (SiO₂, 0-50% EtOAc/hexane)provided 61 mg of a ca. 1:1 mixture of products tert-butyl7-(5-chloro-2-(2-(5-((4-methoxybenzyl)oxy)-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(3) and tert-butyl7-(5-chloro-2-(2-(2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(4).

Compounds made using one or more of the general methods described aboveare shown in Table 3. Where provided, characterization data is to theright of the compounds.

Example 4. Specific Examples Example 4A. Synthesis of Compound 1188,7-(5-chloro-2-(3-(5-cyano-6-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide

A solution of6-chloro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(1, 10.0 g, 45.45 mmol) in Dimethyl sulfoxide (200 mL) was purged withargon gas for 10 minutes. 18-crown-6 ether (17.99 g, 68.18 mmol), andPotassium fluoride (13.2 g, 227.25 mmol) were added to reaction mixtureand purging continued for 5 minutes. Reaction mixture was then stirredin preheated oil bath at 160° C. for 2 h. Reaction mixture cooled down,poured on to ice cold water and extracted with ethyl acetate. Ethylacetate layer was washed with brine solution, dried over anhydroussodium sulphate and concentrated under reduced pressure to get crudeproduct. The crude product obtained was triturated with diethyl etherand dried to get pure6-fluoro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(2) as light brown solid. Yield: 7.3 g, 78%; MS (ESI) m/z 205.14 [M+1]+.

To a solution of6-fluoro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile(2, 3.70 g, 18.13 mmol) and Potassium carbonate (4.96 g, 36.27 mmol) inN,N-Dimethylformamide (74.0 mL), tert-butyl7-(2-(3-bromoprop-1-yn-1-yl)-5-chlorophenyl)thieno[3,2-b]pyridine-3-carboxylate(3, 5.85 g, 12.69 mmol) was added at 0° C. and reaction mixture wasallowed to come at room temperature over a period of 1 h. Aftercompletion, the reaction mixture was poured onto ice cold water. Solidprecipitated out was filtered, and dried to get crude product. The crudeproduct was purified by column chromatography using silica gel (100-200mesh) and 80 to 90% Ethyl acetate in hexanes as eluents. The desiredfractions were concentrated under reduced pressure to get solid. Solidobtained was triturated with methanol and dried to afford tert-butyl7-(5-chloro-2-(3-(5-cyano-6-fluoro-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(4) as pale yellow solid. Yield: 4.25 g, 40%; MS (ESI) m/z 586.32[M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.68 (d, J=4.80 Hz,1H), 8.51 (s, 1H), 7.74 (d, J=8.40 Hz, 1H), 7.67-7.63 (m, 3H), 7.40 (d,J=4.80 Hz, 1H), 4.88 (s, 2H), 2.18 (s, 3H), 1.59 (s, 9H).

To a solution of tert-butyl7-(5-chloro-2-(3-(5-cyano-6-fluoro-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(4, 0.13 g, 0.22 mmol) in dichloromethane (1.0 mL),2,2,2-trifluoroacetic acid (1.0 mL) was added at 0° C., and reactionmixture was stirred at room temperature for 6 h. After completion,reaction mixture concentrated under reduced pressure to get solid. Thesolid obtained was triturated with diethyl ether and dried to7-(5-chloro-2-(3-(5-cyano-6-fluoro-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (5) as off white solid. Yield: 0.090 g, 81%; MS (ESI) m/z 530.12[M+1]+. 1H-NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.75 (d, J=5.44 Hz,1H), 8.59 (s, 1H), 7.76 (d, J=8.44 Hz, 1H), 7.69-7.68 (m, 2H), 7.52 (d,J=4.36 Hz, 1H), 4.87 (s, 2H), 2.13 (s, 3H).

To a solution of7-(5-chloro-2-(3-(5-cyano-6-fluoro-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (5, 0.10 g, 0.189 mmol) and1-(3,3-difluorocyclobutyl)-N-methylpiperidin-4-amine (6, 0.077 g, 0.37mmol) in N-methyl-2-pyrrolidone (1.5 mL) was addedN,N-diisopropylethylamine (0.064 mL, 0.37 mmol). The reaction mixturewas stirred at room temperature for 72 h. After completion, reactionmixture was directly purified by preparative HPLC to afford7-(5-chloro-2-(3-(5-cyano-6-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (7) as a yellow solid. Yield: 0.050 g, 44%; MS (ESI) m/z, 714.50[M+1]+; 1H-NMR (400 MHz, DMSO-d6) δ 9.80 (bs, 1H), 8.76 (s, 1H), 8.75(s, 1H), 8.65 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.70-7.67 (m, 2H), 7.54(d, J=4.8 Hz, 1H), 4.83 (s, 2H), 4.56 (bs, 1H), 3.56 (bs, 4H), 3.11 (bs,1H), 3.06 (s, 3H), 3.05 (bs, 4H), 2.13 (bs, 4H), 2.11 (s, 3H).

To a solution of7-(5-chloro-2-(3-(5-cyano-6-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (7, 1.70 g, 2.377 mmol) and methanesulfonamide (8, 0.564 g, 5.94mmol) in dichloromethane (17.0 mL) were added1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.737 g,4.754 mmol) and 4-(dimethylamino) pyridine (0.725 g, 5.94 mmol) at 0° C.The reaction mixture was stirred at room temperature for 14 h. Aftercompletion, the reaction mixture was diluted with water and extractedwith dichloromethane. The organic layer was dried over anhydrous sodiumsulphate, filtered and concentrated to get crude compound. The crudecompound was purified by preparative HPLC to afford7-(5-chloro-2-(3-(5-cyano-6-((1-(3,3-difluorocyclobutyl)piperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)-N-(methylsulfonyl)thieno[3,2-b]pyridine-3-carboxamide(Cpd. No. 1188) as a yellow solid. Yield: 1.20 g, 63%; MS (ESI) m/z791.62 [M+1]+; ¹H-NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 8.81-8.78 (m,3H), 7.77 (d, J=8.40 Hz, 1H), 7.71-7.67 (m, 2H), 7.62 (d, J=4.80 Hz,1H), 4.83 (s, 2H), 4.59 (bs, 1H), 3.74-3.54 (m, 6H), 3.08 (s, 3H),2.98-2.88 (m, 6H), 2.11-2.05 (m, 4H), 2.00 (s, 3H).

Example 4B. Synthesis of Compound 1141,7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid

Benzyl methyl(piperidin-4-yl)carbamate (2, 0.990 g, 3.99 mmol),2,2-difluoropropyl trifluoromethanesulfonate (1, 1.09 g, 4.78 mmol),potassium carbonate (1.10 g, 7.97 mmol), and 1,4-dioxane (15 mL) werecombined in a 100 mL round bottom flask with a stirbar under argon. Theresulting mixture was stirred vigorously at room temperature under argonfor 17 h. The reaction mixture was filtered through Celite and thefilter cake was washed thoroughly with ethyl acetate. The filtrate wasconcentrated on a rotary evaporator. The residue was taken up indichloromethane and purified via silica gel chromatography (5-60% ethylacetate in hexanes) to afford benzyl(1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)carbamate (3) as acolorless oil. Yield: 958 mg, 74%; MS (ESI) m/z 327.3 [M+1]+; ¹H NMR(400 MHz, Chloroform-d) δ 7.40-7.27 (m, 5H), 5.14 (s, 2H), 4.12-3.81 (m,1H), 2.99 (d, J=11.2 Hz, 2H), 2.82 (s, 3H), 2.66 (t, J=13.7 Hz, 2H),2.32 (bs, 2H), 1.86-1.68 (m, 2H), 1.70-1.50 (m, 5H).

Benzyl (1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)carbamate (3, 255mg, 0.781 mmol) was dissolved with stirring in THF (15 mL) in a 100 mLround bottom flask. A combination vacuum/argon/hydrogen manifold wasattached and the atmosphere in the flask was removed and replaced withargon twice. 10% palladium on carbon (41.6 mg, 0.039 mmol) was added andthe atmosphere in the flask was removed and replaced with hydrogentwice. The resulting mixture was stirred vigorously under hydrogen atroom temperature for 45 min. The reaction mixture was filtered throughCelite and the filter cake washed thoroughly with diethyl ether. Thefiltrate was concentrated on a rotary evaporator at room temperature toafford 1-(2,2-difluoropropyl)-N-methylpiperidin-4-amine (4) as acolorless oil with some black carbon impurities. Yield: 150 mg,quantitative yield; MS (ESI) m/z 193.2 [M+1]+; ¹H NMR (400 MHz,Chloroform-d) δ 2.94-2.86 (m, 2H), 2.65 (t, J=13.6 Hz, 2H), 2.42 (s,3H), 2.38-2.21 (m, 3H), 1.88-1.79 (m, 2H), 1.62 (t, J=18.7 Hz, 3H),1.42-1.30 (m, 2H); ¹⁹F NMR (377 MHz, Chloroform-d) 6-91.92 (qt, J=19.0,13.6 Hz, 2F).

A mixture of tert-butyl7-(5-chloro-2-(3-(5-cyano-6-fluoro-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(5, 100 mg, 0.17 mmol), 1-(2,2-difluoropropyl)-N-methylpiperidin-4-amine(4, 98 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.71 mmol)in N,N-dimethylformamide (2 mL) was stirred at 50° C. over the weekend.The resulting mixture was concentrated and purified via columnchromatography (silica, ethyl acetate/dichloromethane=0-40%) to affordtert-butyl7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(6) as a yellow solid. Yield: 98 mg, 76%; MS (ESI) m/z 758.2 [M+1]+.

tert-Butyl7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylate(6, 97 mg, 0.13 mmol) was dissolved in trifluoroacetic acid (3 mL). Thereaction was stirred at room temperature for 5 h. The resulting mixturewas concentrated. The crude was purified via reversed-phase HPLC (C₁₈,acetonitrile/water=15-45%) to afford7-(5-chloro-2-(3-(5-cyano-6-((1-(2,2-difluoropropyl)piperidin-4-yl)(methyl)amino)-2-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)prop-1-yn-1-yl)phenyl)thieno[3,2-b]pyridine-3-carboxylicacid (1141) as a yellow solid. Yield: 68 mg, 75%; MS (ESI) m/z 702.2[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (d, J=4.8 Hz, 1H), 8.74 (s,1H), 8.65 (s, 1H), 7.78-7.74 (m, 1H), 7.71-7.67 (m, 2H), 7.55 (d, J=4.8Hz, 1H), 4.83 (s, 2H), 3.11 (s, 3H), 2.09 (s, 3H), 1.78 (t, J=19.5 Hz,3H).

Example 4C. Synthesis of Compound 634,7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylicacid

A suspension of copper(I) bromide (89.8 g, 620.1 mmol) and tert-butylnitrite (63.8 mL, 620.1 mmol) in acetonitrile (2500 mL) was heated at65° C. for 15 min. A solution of2-bromo-4-fluoro-6-(trifluoromethyl)aniline (1, 100 g, 387.6 mmol) inacetonitrile was added and heated the reaction mixture at 65° C. for 1h. After completion, the reaction mass was quenched with water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulphate, filtered and concentrated under reduced pressure to getthe crude material. The crude compound was purified by columnchromatography using 0-5% ethyl acetate in hexanes over silica gel(100-200 mesh) to afford 1,2-dibromo-5-fluoro-3-(trifluoromethyl)benzene(2) as off white solid. Yield: 70.0 g, 55%; no ionization in LCMS; ¹HNMR (400 MHz, CDCl₃) δ 7.60 (dd, J=7.32, 2.84, 1H), 7.43 (dd, J=8.24,2.80, 1H).

To a solution of 2,2,6,6-tetramethylpiperidine (7.09 mL, 43.61 mmol) indry tetrahydrofuran (100 mL) was added n-butyllithium (1.2 M, 27.25 mL,32.71 mmol) drop wise at −78° C. under argon atmosphere. The reactionmixture was warmed to 0° C. and stirred for 30 min It was again cooledto −78° C. and a solution of1,2-dibromo-5-fluoro-3-(trifluoromethyl)benzene (2, 10.0 g, 31.15 mol)in dry tetrahydrofuran (70 mL) was added at −100° C. and the reactionmixture was stirred for 45 min at −100° C. Carbon dioxide gas wasbubbled through the reaction mass at this temperature for 15 min and itwas gradually warmed to room temperature in 2 h. After completion, thereaction mixture was quenched with water and washed with diethyl ether.The aqueous layer was acidified to pH ˜3-2 with 6 N aqueous hydrogenchloride, extracted with ethyl acetate, washed the organic layer, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford 2,3-dibromo-6-fluoro-4-(trifluoromethyl)benzoic acid(3) as brown solid. Yield: 10.0 g, crude, 87%; MS (ESI) m/z 362.9[M−1]−.

To a solution of 2,3-dibromo-6-fluoro-4-(trifluoromethyl)benzoic acid(3, 27.0 g, 75.8 mmol) and acetamidine hydrochloride (4, 9.31 g, 98.5mmol) in N,N-dimethylformamide (180 mL),0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (36.5 g, 98.5 mmol) and N,N-diisopropylethyl amine(32.25 mL, 221.9 mmol) were added at −10° C. and stirred for 3 h at 0°C. After completion, the reaction mass was quenched with ice-water andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate and concentrated to dryness under reduced pressure. Theresidue was washed with pentanes to afford2,3-dibromo-6-fluoro-N-(1-iminoethyl)-4-(trifluoromethyl)benzamide (4)as a brown gum. Yield: 30 g (crude); MS (ESI)) m/z 404.8 [M+1]+.

To a solution of2,3-dibromo-6-fluoro-N-(1-iminoethyl)-4-(trifluoromethyl)benzamide (4,30.0 g, 74.4 mmol) in tetrahydrofuran (250 mL), sodium hydride (60%)(5.9 g, 148.8 mmol) was added at 0° C., warmed to room temperature andcontinued to stir at room temperature for 16 h. After completion, thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate andconcentrated to dryness under reduced pressure. The residue was washedwith diethyl ether to afford5,6-dibromo-2-methyl-7-(trifluoromethyl)quinazolin-4(3H)-one (5) aswhite solid. Yield: 9.95 g, 35%; MS (ESI) m/z 383.01 [M−1]−.

To a stirred solution of5,6-dibromo-2-methyl-7-(trifluoromethyl)quinazolin-4(3H)-one (5, 6.0 g,15.62 mmol) in dimethylformamide (90 mL), copper(I) cyanide (1.53 g,17.18 mmol) was added at room temperature and the reaction mixture washeated and stirred at 90° C. for 2 h. After completion, the reactionmass was cooled to room temperature, diluted with ethyl acetate andwashed with water and 1 N aqueous hydrogen chloride. The organic layerwas separated, dried over sodium sulphate and concentrated under reducedpressure. The crude compound was purified by Combi flash (40 g, Redi Sepcolumn) using 70% ethyl acetate in hexanes as eluent. The desiredfractions were concentrated under reduced pressure to afford6-bromo-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(6) as yellow solid. Yield: 3.2 g, 62.7%; MS (ESI) m/z 330.06 [M−1]−.

To a stirred solution of6-bromo-2-methyl-4-oxo-7-(trifluoromethyl)-3,4-dihydroquinazoline-5-carbonitrile(6, 2.0 g, 6.0 mmol) in N,N-dimethylformamide (25.0 mL) was addedpotassium carbonate (2.48 g, 18.0 mmol) at room temperature and themixture was stirred for 20 min. Then tert-butyl7-(2-(2-bromoethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(7, 2.91 g, 6.0 mmol) was added to the reaction mixture at roomtemperature and stirring was continued for 16 h. After completion, thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was washed with water and saturated brine,dried over anhydrous sodium sulphate, filtered and concentrated. Thecrude product was purified by column chromatography using silica gel(100-200 mesh) and 70% ethyl acetate in hexanes as eluent. The desiredfractions were concentrated under reduced pressure to afford tert-butyl7-(2-(2-(6-bromo-5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(8) as a white solid. Yield: 1.7 g, 70%; MS (ESI) m/z 731.14 [M−1]−.

To a solution of tert-butyl7-(2-(2-(6-bromo-5-cyano-2-methyl-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)-5-chlorophenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(8, 0.20 g, 0.273 mmol) in N-Methyl-2-pyrrolidone (5.0 mL) was added1-methylpiperazine (9, 0.06 mL, 0.546 mmol) and the reaction mixture wasdegassed by argon for 10 min. Then copper(I) iodide (0.005 g, 0.027mmol) and 1,10-phenanthroline (0.009 g, 0.054 mmol) was added andreaction mixture was heated at 150° C. for 6 h. After completionreaction mixture was diluted with water, and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulphate,filtered and concentrated to get crude compound. Crude compound obtainedwas purified by column chromatography using silica gel (100-200 mesh)and 3-4% methanol in dichloromethane to afford tert-butyl7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(10) as white solid. Yield: 0.08 g, 39%; MS (ESI) m/z, 751.23 [M−1]−.

To a solution tert-butyl7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylate(10, 0.10 g, 0.132 mmol) in dichloromethane (1.5 mL),2,2,2-trifluoroacetic acid (0.5 mL) was added at 0° C., and reactionmixture was stirred for 12 h at room temperature. After completion,reaction mixture concentrated under reduced pressure to get the crudecompound. The crude compound was purified by preparative HPLC to afford7-(5-chloro-2-(2-(5-cyano-2-methyl-6-(4-methylpiperazin-1-yl)-4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)ethoxy)phenyl)-5-methylthieno[3,2-b]pyridine-3-carboxylicacid (634) as white solid. Yield: 0.020 g, 21%; MS (ESI) m/z 697.13[M+1]+. ¹H-NMR (400 MHz, DMSO-d₆) δ 13.51 (bs, 1H), 9.75 (bs, 1H), 8.23(s, 1H), 7.92 (s, 1H), 7.61-7.58 (t, J=6.5 Hz, 1H), 7.42-7.41 (t, J=6.5Hz, 2H), 7.37 (d, J=8.92 Hz, 1H), 4.40 (t, J=6.16 Hz, 2H), 4.24 (t,J=6.12, 2H), 3.83 (m, 2H), 3.49 (m, 2H), 3.24 (m, 2H), 3.03 (m, 2H),2.28 (s, 3H), 2.71 (s, 3H), 1.82 (s, 3H)

TABLE 3 Other Compounds Compound Characterization 1

MS (ESI) m/z 436.26 [M + 1]+; UPLC: 99.88%; 1H NMR (400 MHz, DMSO-d6) δ12.94 (s, 1H), 8.95 (s, 1H), 8.59 (d, J = 5.2 Hz, 1H), 7.89-7.86 (m,2H), 7.82 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.43-7.38 (m, 2H), 7.27 (d,J = 2.6 Hz, 1H), 7.19 (d, J = 8.92 Hz, 1H), 4.34 (s, 4H), 2.23 (s, 3H) 2

MS (ESI) m/z 437.16 [M + 1]+; UPLC: 97.10%; 1H NMR (400 MHz, DMSO-d6) δ12.97 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H),7.77-7.75 (m, 1H), 7.71-7.68 (m, 2H), 7.57 (d, J = 7.7 Hz, 1H),7.41-7.38 (m, 2H), 7.34 (d, J = 3.7 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H),4.32 (s, 4H) 3

MS (ESI) m/z 439.25 [M + 1]+; UPLC: 99.82%; 1H NMR (400 MHz, DMSO-d6) δ12.85 (bs, 1H), 8.17-8.14 (m, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.88 (d,J = 7.8 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.42-7.36 (m, 4H), 7.34 (d, J= 2.5 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 4.32-4.30 (m, 4H) 4

MS (ESI) m/z 439.2 [M + 1]+; UPLC: 96.95%; 1H NMR (400 MHz, DMSO-d6) δ13.07 (bs, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H),7.80-7.75 (m, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.43-7.38 (m,2H), 7.35 (d, J = 2.6 Hz, 1H), 7.29-7.24 (m, 1H), 7.20 (d, J = 8.8 Hz,1H), 4.29 (dd, J = 14.0, 4.44 Hz, 4H) 5

MS (ESI) m/z 421.21 [M + 1]+; UPLC: 97.35%; 1H NMR (400 MHz, DMSO-d6) δ13.05 (s, 1H), 9.01 (s, 1H), 8.62 (d, J = 5.3 Hz, 1H), 7.97-7.96 (m,2H), 7.90 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.45-7.39 (m,2H), 7.34 (d, J = 2.6 Hz, 1H), 7.27 (d, J = 7.4 Hz, 1H), 7.20 (d, J =8.92 Hz, 1H), 6.50 (d, J = 7.32 Hz, 1H), 4.32-4.30 (m, 4H) 6

MS (ESI) m/z 421.21 [M + 1]+; UPLC: 97.08%; 1H NMR (400 MHz, DMSO-d6) δ13.04 (s, 1H), 9.31 (s, 1H), 8.69 (d, J = 4.72 Hz, 1H), 7.95 (s, 1H),7.89 (d, J = 7.56 Hz, 1H), 7.61-7.57 (m, 1H), 7.42-7.38 (m, 2H), 7.34(s, 1H), 7.20 (d, J = 8.76 Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 4.31 (s,4H) 7

MS (ESI) m/z 421.18 [M + H]+; UPLC: 99.14%; 1H NMR (400 MHz, DMSO-d6) δ13.03 (s, 1H), 8.76 (s, 1H), 8.07 (d, J = 8.04 Hz, 1H), 7.98 (s, 1H),7.91 (d, J = 7.8 Hz, 1H), 7.69-7.66 (m, 1H), 7.62 (d, J = 7.76 Hz, 1H),7.44 (t, J = 7.72 Hz, 1H), 7.40-7.34 (m, 2H), 7.23-7.19 (m, 2H), 6.37(d, J = 7.2 Hz, 1H), 4.32 (s, 4H) 8

MS (ESI) m/z 583.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.46 (bs,1H), 8.84 (d, J = 4.4 Hz, 1H), 8.47 (s, 1H), 7.85 (s, 1H), 7.71-7.22 (m,6H), 4.39- 4.37 (m, 2H), 4.23-4.20 (m, 2H), 1.73 (s, 3H) 9

MS (ESI) m/z 420.37 [M + H]+; UPLC: 99.10%; 1H NMR (400 MHz, DMSO-d6) δ13.07 (s, 1H), 8.18 (d, J = 8.04 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J = 7.7Hz, 1H), 7.68 (t, J = 7.0 Hz, 1H), 7.63-7.58 (m, 2H), 7.50-7.42 (m, 2H),7.40-7.34 (m, 2H), 7.20 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H),6.37 (d, J = 7.36 Hz, 1H), 4.31-4.27 (m, 4H). 10

MS (ESI) m/z 421.21 [M + 1]+; UPLC: 99.17%; 1H NMR (400 MHz, DMSO-d6) δ8.89-8.87 (m, 1H), 8.48 (dd, J = 8.0, 1.5 Hz, 1H), 7.99 (s, 1H), 7.90(d, J = 7.7 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.49-7.33 (m, 5H), 7.19(d, J = 8.7 Hz, 1H), 6.43 (d, J = 7.56 Hz, 1H), 4.30 (s, 4H) 11

MS (ESI) m/z 421.21 [M + 1]+; UPLC: 98.51%; 1H NMR (400 MHz, DMSO-d6) δ12.98 (bs, 1H), 8.11 (dd, J = 8.0, 1.2 Hz, 1H), 8.10 (s, 1H), 7.94 (s,1H), 7.89 (d, J = 7.6 Hz, 1H), 7.83-7.78 (m, 1H), 7.63 (d, J = 8.0 Hz,1H), 7.54-7.50 (m, 2H), 7.41-7.37 (m, 2H), 7.35 (d, J = 2.6 Hz, 1H),7.20 (d, J = 8.8 Hz, 1H), 4.32 (s, 4H) 12

MS (ESI) m/z 422.22 [M + 1]+; UPLC: 97.46%; 1H NMR (400 MHz, DMSO-d6) δ13.02 (bs, 1H), 8.94 (d, J = 2.72 Hz, 1H), 8.49 (dd, J = 7.84, 1.6 Hz,1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.87 (d, J = 7.68 Hz, 1H), 7.60-7.53(m, 2H), 7.48-7.34 (m, 3H), 7.20 (d, J = 8.72 Hz, 1H), 4.33 (s, 4H) 13

MS (ESI) m/z 422.18 [M + 1]+; UPLC: 98.27%; 1H NMR (400 MHz, DMSO-d6) δ12.94 (bs, 1H), 9.26 (s, 1H), 8.82 (d, J = 5.6 Hz, 1H), 8.19 (s, 1H),7.92 (s, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.59-7.54 (m, 2H), 7.41-7.37 (m,2H), 7.33 (d, J = 2.6 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 4.33 (s, 4H) 14

MS (ESI) m/z 422.24 [M + 1]+; UPLC: 93.73%; 1H NMR (400 MHz, DMSO-d6) δ9.39 (s, 1H), 9.30 (s, 1H), 7.94 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.66(d, J = 7.6 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.44- 7.38 (m, 2H), 7.32(s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 7.5 Hz, 1H), 4.32 (s,4H) 15

MS (ESI) m/z 422.18 [M + 1]+; UPLC: 96.38%; 1H NMR (400 MHz, DMSO-d6) δ13.03 (bs, 1H), 9.43 (d, J = 5.4 Hz, 1H), 8.19 (d, J = 5.0 Hz, 1H), 7.95(s, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.50 (d, J= 7.6 Hz, 1H), 7.45-7.33 (m, 3H), 7.20 (d, J = 8.8 Hz, 1H), 6.76 (d, J =7.4 Hz, 1H), 4.34-4.31 (m, 4H) 16

MS (ESI) m/z 642.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J =4.7 Hz, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 7.63 (dd, J = 8.8, 2.3 Hz, 1H),7.51 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 9.1 Hz,1H), 4.67 (bs, 2H), 4.45 (t, J = 5.2 Hz 2H), 4.29 (t, J = 3.9 Hz 2H),2.93 (s, 6H), 1.78 (s, 3H) 17

MS (ESI) m/z 423.23 [M + 1]+; UPLC: 92.07%; 1H NMR (400 MHz, DMSO-d6) δ9.43 (s, 1H). 9.39 (s, 1H), 8.58 (s, 1H), 7.86 (s, 1H), 7.85 (d, J = 7.7Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.41-7.37 (m, 2H), 7.33 (d, J = 2.6Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 4.31 (s, 4H) 18

MS (ESI) m/z 423.23 [M + 1]+; UPLC: 99.81%; 1H NMR (400 MHz, DMSO-d6) δ13.07 (bs, 1H), 9.48 (d, J = 5.0 Hz, 1H), 8.33 (s, 1H), 8.23 (d, J = 5.1Hz, 1H), 7.93 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 6.2 Hz,1H), 7.44-7.34 (m, 3H), 7.20 (d, J = 8.8 Hz, 1H), 4.33 (s, 4H) 19

MS (ESI) m/z 423.23 [M + 1]+; UPLC: 96.78%; 1H NMR (400 MHz, DMSO-d6) δ8.99 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.32 (s, 1H), 7.95(s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.40-7.36(m, 2H), 7.34 (d, J = 2.7 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 4.36-4.35(m, 4H) 20

MS (ESI) m/z 422.22 [M + 1]+; UPLC: 97.46%; 1H NMR (400 MHz, DMSO-d6) δ12.98 (bs, 1H), 8.74 (d, J = 8.0 Hz, 1H), 8.36 (s, 1H), 7.98 (d, J = 8.1Hz, 1H), 7.94 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.7 Hz,1H), 7.42-7.38 (m, 2H), 7.35 (d, J = 2.6 Hz, 1H), 7.20 (d, J = 8.8 Hz,1H), 4.35 (s, 4H) 21

MS (ESI) m/z 422.18 [M + 1]+; UPLC: 98.77%; 1H NMR (400 MHz, DMSO-d6) δ12.96 (bs, 1H), 8.79 (dd, J = 4.1, 1.1 Hz, 1H), 8.06-8.04 (m, 2H), 7.93(s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.81-7.78 (m, 1H), 7.60-7.58 (m, 1H),7.42-7.38 (m, 2H), 7.34 (d, J = 2.6 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H),4.34 (s, 4H) 22

MS (ESI) m/z 585.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =4.8 Hz, 1H), 8.44 (s, 1H), 8.04 (d, J = 9.72 Hz, 1H), 7.61-7.59 (dd, J =2.56 Hz, J = 2.64 Hz, 1H), 7.50-7.36 (m, 4H), 4.42 (t, J = 4.56 Hz, 2H),4.28 (t, J = 4.64 Hz, 2H), 1.87 (s, 3H) 23

MS (ESI) m/z 438.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H),8.53 (s, 1H), 8.29 (s, 1H), 7.93 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.83(dd, J = 2.12, 8.44 Hz, 1H), 7.77 (d, J = 1.96 Hz, 1H), 7.56 (d, J =7.72 Hz, 1H), 7.43 (t, J = 15.5 Hz, 1H), 7.33 (d, J = 8.64 Hz, 1H), 4.44(d, J = 4.84 Hz, 2H), 4.40 (d, J = 4.68 Hz, 2H) 24

MS (ESI) m/z 485.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H),9.11 (s, 1H), 8.56 (s, 1H), 8.01 (s, 1H), 7.74-7.77 (m, 1H), 7.32-7.40(m, 3H), 7.13-7.16 (m, 2H), 4.29 (s, 4H), 1.55 (s, 3H) 25

MS (ESI) m/z 457.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H),9.19 (s, 1H), 8.86 (s, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 7.99-8.07 (m,2H), 7.72 (s, 1H), 7.58-7.63 (m, 2H), 7.04 (s, 1H), 5.48 (s, 2H) 26

MS (ESI) m/z 530.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H),8.88 (s, 1H), 8.02 (s, 1H), 7.58-7.90 (m, 2H), 7.64 (s, 2H), 7.54 (s,4H), 7.30-7.36 (m, 4H), 7.16 (s, 1H), 4.26 (s, 4H) 27

MS (ESI) m/z 471.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H),8.38 (s, 1H), 8.20 (s, 1H), 8.039 (d, J = 8.56 1H), 7.87-7.86 (m, 1H),7.82-7.81 (m, 1H), 7.62-7.58 (m, 1H), 7.43-7.39 (m, 2H), 7.33 (d, J =2.64 Hz, 1H), 7.21 (d, J = 8.84 Hz, 1H), 4.35 (s, 4H) 28

MS (ESI) m/z 496.36 [M + 1]+UPLC: 99.32%; 1H NMR (400 MHz, DMSO-d6) δ12.97 (s, 1H), 8.17-8.15 (m, 2H), 8.04 (d, J = 8.56 Hz, 1H), 7.90- 7.89(m, 1H), 7.84-7.82 (m, 1H), 7.61-7.58 (m, 1H), 7.52-7.25 (m, 4H), 7.21(d, J = 8.88 Hz, 1H), 4.35 (s, 4H) 29

MS (ESI) m/z 448.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H),8.63(d, J = 4.47 Hz, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.63(d, J = 3.64 Hz, 1H), 7.49-7.45 (m, 2H), 7.25 (d, J = 8.68 Hz, 1H), 4.38(m, 4H) 30

MS (ESI) m/z 504.39 [M + 1]+. UPLC: 99.59%; 1H NMR (400 MHz, DMSO-d6) δ8.96 (s, 1H), 8.81(d, J = 4.88 Hz, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 7.91(s, 1H), 7.61-7.59 (dd, J = 2.60, 8.88 Hz, 1H), 7.49-7.46 (m, 2H), 7.35(d, J = 8.96 Hz, 1H), 4.40-4.38 (t, J = 5.00 Hz, 2H), 4.25-4.23 (t, J =4.84 Hz, 2H) 31

MS (ESI) m/z 457.36 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H),8.92 (s, 1H), 8.42 (s, 1H), 7.86 (s, 1H), 7.81 (d, J = 11.08 Hz, 1H),7.57 (d, J = 7.8 Hz, 1H), 7.42-7.37 (m, 2H), 7.30 (d, J = 2.72 Hz, 1H),7.21 (d, J = 8.88 Hz, 1H), 4.61 (t, J = 5.12 Hz, 2H), 4.42 (t, J = 10.08Hz, 2H), 2.11-2.05 (m, 1H), 1.03- 0.99 (m, 2H), 0.77-0.72 (m, 2H). 32

MS (ESI) m/z 515.33 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H),9.13 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 7.92 (s, 1H), 7.86 (t, J =5.76 Hz, 2H), 7.61 (d, J = 7.72 Hz, 1H), 7.43-7.39 (m, 2H), 7.34 (d, J =2.44 Hz, 1H), 7.2 (d, J = 8.84 Hz, 1H), 4.35 (m, 4H), 2.59 (s, 3H) 33

MS (ESI) m/z 511.34 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H),7.84 (d, J = 7.6 Hz, 2H), 7.74-7.47 (t, J = 5.6 Hz, 1H), 7.43-7.36 (m,3H), 7.25 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 4.37 (d, J =4.4 Hz ,2H), 4.33 (d, J = 3.6 Hz, 2H), 2.89 (s, 3H) 37

MS (ESI) m/z 510.40 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H),8.13 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.83-7.84 (m, 2H),7.36-7.72 (m, 4H), 7.27-7.28 (m, 1H), 7.21 (d, J = 8.8 Hz, 1H), 4.35 (s,4H), 2.22 (s, 3H) 40

MS (ESI) m/z 603.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.38 (bs, 1H), 8.28 (s, 1H), 8.01 (bs, 1H), 7.63 (d, J =8.4 Hz, 1H), 7.54 (d, J = 11.4 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 4.43(t, J = 4.4 Hz, 2H), 4.25 (t, J = 4.4 Hz, 2H), 1.73 (s, 3H) 41

MS (ESI) m/z 441.24 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H),9.1 (s, 1H), 8.6 (s, 1H), 8.57 (s, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.75(s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.50-7.44 (m, 3H), 7.36 (d, J = 1.76Hz, 1H), 6.46-6.39 (m, 1H), 6.27 (d, J = 16.09 Hz, 1H), 4.73 (d, J =5.12 Hz, 2H) 42

MS (ESI) m/z 445.39 [M + 1]+UPLC: 99.76%; 1H NMR (400 MHz, DMSO-d6) δ13.01 (s, 1H), 9.12 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 7.69 (s, 1H),7.64-7.62 (m, 1H), 7.48 (d, J = 7.72 Hz, 1H), 7.41-7.34 (m, 3H), 7.19(s, 1H), 3.90-3.87 (m, 2H), 2.55-2.50 (m, 2H), 1.80-1.74 (m, 2H) 43

MS (ESI) m/z 457.36 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.08 (b, 1H),9.14 (s, 1H), 8.56 (d, J = 4.52 Hz, 2H), 7.92 (d, J = 7.44 Hz, 1H), 7.88(s, 1H), 7.62-7.54 (m, 2H), 7.34 (dd, J = 8.44 Hz, 1H), 7.23 (d, J = 2.2Hz, 1H), 7.03 (d, J = 8.48 Hz, 1H), 4.02-3.97 (m, 1H), 3.79- 3.74 (m,1H), 1.94 (q, J = 6.68 Hz, 1H), 1.61 (q, J = 6.76 Hz, 1H), 1.07 (t, J =7.04 Hz, 2H) 46

MS (ESI) m/z 638.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H),8.82 (d, J = 4.84 Hz, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H),7.62-7.59 (dd, J = 2.48 Hz, J = 2.44 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H),7.40-7.30 (m, 2H), 4.51- 4.46 (m, 4H) 47

MS (ESI) m/z 558.95 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H),8.85 (d, J = 4.68 Hz, 1H), 8.57 (d, J = 1.16 Hz, 1H), 8.23 (d, J = 1.23Hz, 1H), 8.17 (s, 1H), 7.61-7.58 (dd, J = 2.72 Hz, J = 2.68 Hz, 1H),7.49 (d, J = 4.72 Hz, 1H), 7.40 (d, J = 2.72 Hz, 1H), 7.36 (d, J = 8.96Hz, 1H), 4.40 (t, J = 4.40 Hz, J = 4.76 Hz, 2H), 4.18 (t, J = 4.44 Hz, J= 4.28 Hz, 2H), 1.48 (d, J = 3.52 Hz, 3H) 52

MS (ESI) m/z 454.33 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H),8.69 (s, 1H), 8.56 (s, 1H), 8.20 (d, J = 2.64 Hz, 1H), 8.06 (s, 1H),7.51 (dd, J = 8.88 Hz, 1H), 7.37 (d, J = 9 Hz, 1H), 4.68 (t, J = 5.52Hz, 2H), 4.54 (t, J = 5.48 Hz, 2H) 53

MS (ESI) m/z 453.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.99 (b, 1H),9.09 (s, 1H), 8.60 (s, 1H), 8.53 (s, 1H), 7.83 (d, J = 2.52 Hz, 1H),7.62 (d, J = 4.04 Hz, 1H), 7.55 (d, J = 4 Hz, 1H), 7.42-7.40 (m, 1H),7.31 (d, J = 8.96 Hz, 1H), 4.61 (t, J = 5.36 Hz, 2H), 4.58 (t, J = 5.28Hz, 2H) 54

MS (ESI) m/z 454.36 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H),8.63 (s, 1H), 8.57 (s, 1H), 8.25 (bs, 1H), 7.79 (s, 1H), 7.38 (dd, J =8.72 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 4.50 (t, J = 2.96 Hz, 4H). 55

MS (ESI) m/z 534.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H),8.11 (d, J = 8.56 Hz, 1H), 7.96 (d, J = 8.52 Hz, 1H), 7.82 (d, J = 7.68Hz, 1H), 7.48-7.21 (m, 4H), 7.15 (d, J = 9.48 Hz, 2H), 4.30 (s, 4H),3.75 (s, 1H), 1.98 (s, 3H) 56

MS (ESI) m/z 510.73 [M + 1]+; UPLC: 99.83%; 1H NMR (400 MHz, DMSO-d6) δ12.91 (s, 1H), 8.61 (d, J = 4.56 Hz, 1H), 8.14 (d, J = 8.60 Hz, 1H),7.98 (d, J = 8.44 Hz, 2H), 7.59-7.58 (m, 1H), 7.51- 7.23 (m, 4H), 4.39(s, 4H), 2.22 (s, 3H) 57

MS (ESI) m/z 535.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H),8.13(d, J = 8.72 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.49-7.19 (m, 5H),4.32 (s, 4H), 4.06 (s, 1H), 2.08 (s, 3H) 62

MS (ESI) m/z 508.04 [M − 1]−. UPLC: 98.04%; 1H NMR (400 MHz, DMSO-d6) δ12.92 (s, 1H), 8.13 (d, J = 8.64 Hz, 1H), 7.97 (d, J = 8.56 Hz, 1H),7.86 (d, J = 7.84 Hz, 1H), 7.83 (s, 1H), 7.53- 7.20 (m, 6H), 4.35 (s,4H), 2.20 (s, 3H) 63

MS (ESI) m/z 535.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H),7.84-7.79 (m, 2H), 7.61-7.36 (m, 4H), 7.24 (s, 1H), 7.18 (d, J = 8.88Hz, 1H), 4.34 (s, 4H), 2.17 (s, 3H) 64

MS (ESI) m/z 560.18 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.93 (bs,1H), 8.12 (s, 1H), 7.85-7.83 (m, 2H), 7.63-7.19 (m, 7H), 4.35 (s, 4H),2.21 (s, 3H) 66

MS (ESI) m/z 445.13 [M − 1]−; UPLC: 93.91%; 1H NMR (400 MHz, DMSO-d6) δ12.94 (s, 1H), 9.09 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 7.85-7.83 (m,2H), 7.58 (d, J = 7.84 Hz, 1H), 7.44-7.39 (m, 2H), 7.32 (d, J = 2.60 Hz,1H), 7.20 (d, J = 8.88 Hz, 1H) 4.35 (s, 4H) 67

MS (ESI) m/z 423.16 [M + 1]+; UPLC: 97.88%; 1H NMR (400 MHz, DMSO-d6) δ12.98 (bs, 1H), 8.02 (s, 1H), 7.92-7.91 (m, 3H), 7.56-7.55 (m, 1H), 7.44(t, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.8, 2.8 Hz, 1H), 7.33 (d, J = 2.4Hz, 1H), 7.2 (d, J = 8.8 Hz, 1H), 4.32-4.29 (m, 4H), 3.69 (s, 3H) 68

MS (ESI) m/z 424.24 [M + 1]+; UPLC: 97.94%; 1H NMR (400 MHz, DMSO-d6) δ12.98 (bs, 1H), 7.95-7.91 (m, 2H), 7.78 (s, 1H), 7.58-7.55 (m, 1H), 7.44(t, J = 7.6 Hz, 1H), 7.38 (dd, J = 8.8, 2.4 Hz, 1H), 7.34 (d, J = 2.4Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 3.2 Hz, 1H), 6.43 (d, J= 3.2 Hz, 1H), 4.27 (s, 4H), 3.66 (s, 3H) 69

MS (ESI) m/z 424.27 [M + 1]+; UPLC: 98.50%; 1H NMR (400 MHz, DMSO-d6) δ8.00 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.51 (d, J = 7.6Hz, 1H), 7.42-7.34 (m, 4H), 7.18 (d, J = 8.8 Hz, 1H), 6.28 (d, J = 2.8Hz, 1H), 4.28 (s, 4H), 3.97 (s, 3H) 70

MS (ESI) m/z 450.27 [M + 1]+; UPLC: 96.87%; 1H NMR (400 MHz, DMSO-d6) δ12.98 (bs, 1H), 8.97 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 7.89-7.87 (m,3H), 7.54-7.52 (m, 1H), 7.43-7.37 (m, 2H), 7.28 (d, J = 2.8 Hz, 1H),7.18 (d, J = 8.8 Hz, 1H), 4.37-4.24 (m, 4H), 2.60-2.49 (m, 2H), 0.97 (t,J = 7.2 Hz, 3H) 71

MS (ESI) m/z 450.27 [M + 1]+; UPLC: 96.87%; 1H NMR (400 MHz, DMSO-d6) δ12.98 (bs, 1H), 8.97 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 7.89-7.87 (m,3H), 7.54- 7.52 (m, 1H), 7.43-7.37 (m, 2H), 7.28 (d, J = 2.8 Hz, 1H),7.18 (d, J = 8.8 Hz, 1H), 4.37-4.24 (m, 4H), 2.60-2.49 (m, 2H), 0.97 (t,J = 7.2 Hz, 3H) 72

MS (ESI) m/z 435.22 [M + 1]+; UPLC: 95.85%; 1H NMR (400 MHz, DMSO-d6) δ12.98 (bs, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.91-7.89 (m, 2H), 7.78 (t, J= 7.2 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.52- 7.37 (m, 4H), 7.29 (d, J= 2.4 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 4.33 (s, 4H), 2.22 (s, 3H) 73

LCMS Purity: 96.35%, MS: m/z 444.18 [M − 1]−; 1H NMR (DMSO-d6, 400 mHz)δ 12.96 (bs, 1H), 8.09 (s, 1H), 8.02 (m, 1H), 7.92 (m, 3H), 7.85 (d, J =7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.41-7.39 (m, 2H), 7.33 (d, J =2.7 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 4.33 (m, 4H) 74

MS (ESI) m/z 446.22 [M + 1]+; UPLC: 97.68%; 1H NMR (400 MHz, DMSO-d6) δ12.95 (bs, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.15 (s, 1H), 8.09 (s, 1H),7.89-7.84 (m, 3H), 7.57 (d, J = 7.7 Hz, 1H), 7.41-7.38 (m, 2H), 7.33 (d,J = 2.5 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 4.39-4.32 (m, 4H) 75

MS (ESI) m/z 446.25 [M + 1]+; UPLC: 97.45%; 1H NMR (400 MHz, DMSO-d6) δ12.96 (s, 1H), 8.36-8.31 (m, 2H), 8.24 (s, 1H), 7.90 (s, 1H), 7.83 (d, J= 7.8 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H),7.41-7.33 (m, 3H), 7.21 (d, J = 8.8 Hz, 1H), 4.34 (s, 4H) 76

MS (ESI) m/z 439.21 [M + 1]+; UPLC: 99.71%; 1H NMR (400 MHz, DMSO-d6) δ8.08 (s, 1H), 7.94-7.85 (m, 3H), 7.70-7.68 (m, 1H), 7.58 (d, J = 7.86Hz, 1H), 7.53-7.48 (m, 1H), 7.40-7.29 (m, 3H), 7.20 (d, J = 8.8 Hz, 1H),4.33 (s, 4H) 77

MS (ESI) m/z 457.25 [M + 1]+; UPLC: 95.49%; 1H NMR (400 MHz, DMSO-d6) δ12.95 (bs, 1H), 8.07-7.96 (m, 2H), 7.89-7.85 (m, 2H), 7.72-7.67 (m, 1H),7.57 (d, J = 7.8 Hz, 1H), 7.43-7.38 (m, 2H), 7.32 (d, J = 2.6 Hz, 1H),7.20 (d, J = 8.8 Hz, 1H), 4.33-4.30 (m, 4H) 78

MS (ESI) m/z 457.21 [M + 1]+; UPLC: 95.45%; 1H NMR (400 MHz, DMSO-d6) δ12.96 (bs, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H),7.60 (d, J = 7.8 Hz, 1H), 7.44-7.7.33 (m, 4H), 7.28- 7.25 (m, 1H), 7.20(d, J = 9.6 Hz, 1H), 4.31-4.25 (m, 4H) 79

MS (ESI) m/z 437.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H),8.74 (s, 1H), 8.60 (s, 1H), 7.69 (d, J = 2.6 Hz, 1H), 7.40 (dd, J = 8.84Hz, 2.64 Hz, 1H), 7.24 (d, J = 8.96 Hz, 1H), 7.15 (bs, 1H), 7.03 (d, J =3.32 Hz, 1H), 4.53 (s, 4H) 80

MS (ESI) m/z 453.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H),8.56 (s, 2H), 7.87 (s, 1H), 7.72 (s, 1H), 7.51 (d, J = 2.56 Hz, 1H),7.31 (dd, J = 8.8 Hz, 2.56 Hz, 1H), 7.15 (d, J = 8.92 Hz, 1H), 4.45 (t,J = 4.76 Hz, 2H), 4.41 (t, J = 4.72 Hz, 2H) 81

MS (ESI) m/z 454.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.17 (bs,1H), 9.14 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 8.20 (bs, 2H), 7.51 (d, J= 8.00 Hz, 1H), 7.35 (d, J = 8.96 Hz, 1H), 4.66 (bs, 2H), 4.55 (bs, 2H)82

MS (ESI) m/z 450.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.23 (bs,1H), 9.13 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 7.49 (d, J = 2.44 Hz,1H), 7.41 (bs, 1H), 7.17-7.14 (m, 1H), 7.09 (d, J = 8.2 Hz, 1H), 7.04(bs, 1H), 4.49 (t, J = 4.32 Hz, 2H), 4.46 (t, J = 4.56 Hz, 2H), 3.84 (s,3H) 83

MS (ESI) m/z 453.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H),9.12 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.09 (bs, 1H), 7.77 (d, J =2.68 Hz, 2H), 7.36 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.25 (d, J = 8.8 Hz,1H), 4.55 (t, J = 4.8 Hz, 2H), 4.48 (t, J = 5.2 Hz, 2H) 84

MS (ESI) m/z 451.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.60 (bs,1H), 9.09 (s, 1H), 8.52 (s, 1H), 8.25 (s, 1H), 7.52 (dd, J = 8.76 Hz,2.6 Hz, 1H), 7.34 (d, J = 2.64 Hz, 1H), 7.24 (d, J = 8.92 Hz, 1H), 6.52(s, 1H), 4.36 (s, 4H), 3.56 (s, 3H) 85

MS (ESI) m/z 449.36 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H),8.98 (bs, 2H), 8.54 (s, 1H), 8.43 (bs, 1H), 7.67 (bs, 1H), 7.51 (d, J =8.8 Hz, 1H), 7.26 (d, J = 7.84 Hz, 1H), 4.44 (s, 4H) 86

MS (ESI) m/z 483.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H),9.10 (s, 1H), 8.52 (s, 1H), 8.22 (s, 1H), 7.64 (t, J = 8.32 Hz, 1H),7.46(dd, J = 8.8 Hz, 2.56 Hz, 1H), 7.31 (d, J = 2.52 Hz, 1H), 7.21-7.18 (m,2H), 4.32 (s, 4H) 87

MS (ESI) m/z 478.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H),9.08 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 7.57 (s, 1H), 7.45 (dd, J =8.76 Hz, 2.6 Hz, 1H), 7.38 (d, J = 2.72 Hz, 1H), 7.23 (d, J = 8.88 Hz,1H), 6.87 (bs, 1H), 4.38 (bs, 4H), 3.88 (s, 3H) 88

MS (ESI) m/z 478.30 [M + 1]+; 1H NMR (400 mHz, DMSO-d6) δ 13.10 (s, 1H),9.06 (s, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 8.11-8.08 (m,1H), 7.73 (d, J = 2.68 Hz, 1H), 7.37 (dd, J = 8.76 Hz, 2.68Hz, 1H), 7.21(d, J = 8.88 Hz, 1H), 4.44 (s, 4H), 2.95 (d, J = 4.24 Hz, 3H) 89

MS (ESI) m/z 483.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H),9.08 (s, 1H), 8.51 (s, 1H), 8.22 (s, 1H), 7.81-7.77 (m, 1H), 7.51-7.48(m, 2H), 7.35 (d, J = 2.6 Hz, 1H), 7.23 (d, J = 8.92 Hz, 1H), 4.36-4.33(m, 4H) 90

MS (ESI) m/z 479.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H),8.58 (s, 1H), 8.56 (s, 1H), 8.41 (bs, 1H), 7.63 (bs, 1H), 7.41 (dd, J =8.8 Hz, 2.4 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H), 4.47- 4.43 (m, 4H), 3.90(s, 3H) 91

MS (ESI) m/z 483.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.83 (bs,1H), 9.11 (s, 1H), 8.54 (s, 1H), 8.23 (s, 1H), 7.46-7.43 (m, 1H), 7.35(bs, 1H), 7.28 (d, J = 2.56 Hz, 1H), 7.20 (d, J = 8.96 Hz, 1H), 7.07 (t,J = 9.12 Hz, 1H), 4.32 (s, 4H) 92

MS (ESI) m/z 487.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.41 (bs,1H), 9.07 (s, 1H), 8.47 (s, 1H), 7.96 (s, 1H), 7.65 (dd, J = 8.12 Hz,1.72 Hz, 1H), 7.43-7.40 (m, 2H), 7.19-7.17 (m, 2H), 6.79 (d, J = 8.2 Hz,1H), 4.26 (s, 4H), 1.44- 1.38 (m, 1H), 0.70-0.47 (m, 4H) 93

MS (ESI) m/z 472.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (bs,1H), 9.05 (s, 1H), 8.49 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 8.07 (t, J= 1.48 Hz, 1H), 8.01 (t, J = 1.48 Hz, 1H), 7.45 (dd, J = 8.8 Hz, 2.68Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 4.38-4.33(m, 4H) 94

MS (ESI) m/z 472.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.87 (bs,1H), 9.10 (s, 1H), 8.54 (s, 1H), 8.31 (bs, 1H), 7.98 (bs, 1H), 7.72 (bs,1H), 7.62 (bs, 1H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.39 (d, J = 2.4 Hz,1H), 7.22 (d, J = 8.8 Hz, 1H), 4.35 (s, 4H) 95

MS (ESI) m/z 493.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.04 (bs,1H), 9.04 (s, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 7.56 (bs, 2H), 7.41 (dd,J = 8.8 Hz, 2.52 Hz, 1H), 7.34-7.32 (m, 2H), 7.22 (d, J = 8.84 Hz, 1H),4.37-4.33 (m, 4H), 2.45 (s, 3H) 96

MS (ESI) m/z 491.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.97 b(s,1H), 9.09 (s, 1H), 8.52 (s, 1H), 8.31 (s, 1H), 7.36 (dd, J = 8.72, 2.56Hz, 1H), 7.24 (d, J = 2.64 Hz, 1H), 7.17 (d, J = 8.88 Hz, 1H), 7.13 (d,J = 1.64 Hz, 1H), 7.01 (d, J = 1.64 Hz, 1H), 6.16 (s, 2H), 4.35 (s, 4H)97

MS (ESI) m/z 495.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 69.08 (s, 1H),8.50 (s, 1H), 8.13 (s, 1H), 7.41-7.35 (m, 2H), 7.14-7.12 (m, 2H), 6.78(d, J = 12.88 Hz, 1H), 4.27 (t, J = 4.2 Hz, 2H), 4.25 (t, J = 4.08 Hz,2H), 3.62 (s, 3H) 98

MS (ESI) m/z 495.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.56 (bs,1H), 9.07 (d, J = 0.68 Hz, 1H), 8.91 (s, 1H), 8.53 (s, 1H), 8.48 (s,1H), 7.74 (d, J = 2.8 Hz, 1H), 7.49 (dd, J = 8.92 Hz, 2.72 Hz, 1H), 7.28(d, J = 9.0 Hz, 1H), 4.48- 4.44 (m, 4H), 2.41 (s, 3H) 99

MS (ESI) m/z 498.33 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.78 (bs,1H), 8.83 (s, 1H), 8.73 (d, J = 7.84 Hz, 1H), 8.33 (s, 2H), 8.19 (s,1H), 8.07 (d, J = 7.8 Hz, 1H), 7.85-7.81 (m, 1H), 7.76-7.72 (m, 2H),7.52 (dd, J = 8.76, 2.64 Hz, 1H), 7.32 (d, J = 8.92 Hz, 1H), 4.49 (t, J= 4.92 Hz, 2H), 4.37 (t, J = 4.88 Hz, 2H) 100

MS (ESI) m/z 498.33 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J =3.12 Hz, 1H), 8.78 (s, 1H), 8.65 (d, J = 7.24 Hz, 1H), 8.47 (d, J = 1.76Hz, 1H), 8.30 (bs, 2H), 8.15 (s, 1H), 7.89- 7.86 (m, 1H), 7.52-7.49 (m,2H), 7.30 (d, J = 8.8 Hz, 1H), 4.42 (t, J = 4.88 Hz, 2H), 4.32 (t, J =4.72 Hz, 2H). 101

MS (ESI) m/z 501.29 [M + 1]+; 1H NMR (400 mHz, DMSO-d6) δ 9.11 (s, 1H),8.53 (s, 1H), 8.34 (s, 1H), 7.46 (dd, J = 8.88, 2.6 Hz, 1H), 7.36 (t, J= 6.8 Hz, 1H), 7.27 (d, J = 2.68 Hz, 1H), 7.20 (d, J = 8.92 Hz, 2H),4.34 (s, 4H) 102

MS (ESI) m/z 501.29 [M + 1]+; 1H NMR (400 mHz, DMSO-d6) δ 12.88 (s, 1H),8.87 (s, 1H), 8.50 (s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.69 (s, 1H),7.64 (s, 1H), 7.43-7.40 (m, 1H), 7.34 (d, J = 2.16 Hz, 1H), 7.25 (d, J =8.76 Hz, 1H), 4.40 (t, J = 4.68 Hz, 2H), 4.31 (t, J = 4.52 Hz, 2H), 4.23(s, 3H) 103

MS (ESI) m/z 504.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H),11.07 (s, 1H), 9.03 (d, J = 0.68 Hz, 1H), 8.44 (s, 1H), 8.36 (d, J =8.68 Hz, 1H), 8.32 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.50 (dd, J =8.64, 2.12 Hz, 1H), 7.38 (dd, J = 8.88, 2.72 Hz, 1H), 7.27 (d, J = 2.6Hz, 1H), 7.20 (d, J = 8.84 Hz, 1H), 4.35 (s, 4H), 2.19 (s, 3H) 104

MS (ESI) m/z 489.37 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.61 (bs,1H), 9.09 (s, 1H), 8.52 (s, 1H), 8.37 (s, 1H), 7.48 (bs, 1H), 7.37 (bs,1H), 7.33 (dd, J = 8.80, 2.60 Hz, 1H), 7.23 (d, J = 2.60 Hz, 1H), 7.15(d, J = 8.80 Hz, 1H), 4.66 (t, J = 8.72 Hz, 2H), 4.35 (bs, 4H), 3.22 (t,J = 8.68 Hz, 2H) 105

MS (ESI) m/z 503.38 [M + 1]+; 1H NMR (400 mHz, DMSO-d6) δ 9.03 (s, 1H),8.49 (s, 1H), 8.26 (bs, 1H), 7.85 (s, 1H), 7.74 (bs, 1H), 7.53 (s, 1H),7.38 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 9.16Hz, 1H), 4.33 (s, 4H), 1.27 (s, 9H) 106

MS (ESI) m/z 491.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H),8.51 (s, 1H), 8.30 (s, 1H), 7.73 (bs, 1H), 7.68 (bs, 1H), 7.39- 7.36 (m,2H), 7.29 (d, J = 2.6 Hz, 1H), 7.18 (d, J = 8.88 Hz, 1H), 4.64 (t, J =5.12 Hz, 1H), 4.34 (s, 4H), 3.62 (t, J = 5.92 Hz, 2H), 2.76 (t, J = 6.64Hz, 2H) 107

MS (ESI) m/z 507.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H),9.05 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 7.38-7.35 (m, 1H 7.31 (d, J =2.6 Hz, 1H), 7.18-7.16 (m, 2H), 7.10 (d, J = 1.8 Hz, 1H), 4.34 (bs, 4H),3.80 (s, 3H) ), 3.76 (s, 3H) 108

MS (ESI) m/z 511.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H),8.52(s, 1H), 8.36 (s, 1H), 7.57 (d, J = 2.12 Hz, 1H), 7.54 (bs, 1H),7.38 (dd J = 8.88 Hz, 2.72 Hz, 1H), 7.33 (d, J = 2.60 Hz, 2H), 7.18 (d,J = 8.8 Hz, 1H), 4.36 (s, 4H), 3.89 (s, 3H) 109

MS (ESI) m/z 498.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.98 (bs,1H), 9.05 (s, 1H), 8.71 (s, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 8.28 (s,1H), 7.77 (t, J = 54.52 Hz, 1H), 7.49-7.45 (m, 2H), 7.23 (d, J = 8.76Hz, 1H), 4.38 (s, 4H). 110

MS (ESI) m/z 514.40 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 13.11 (bs, 1H),9.03 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.97 (t, J = 1.68 Hz, 1H),7.82 (t, J = 1.36 Hz, 1H), 7.71 (t, J = 1.60 Hz, 2H), 7.43 (dd, J =8.88, 2.76 Hz, 1H), 7.23 (d, J = 8.92 Hz, 1H), 4.36-4.32 (m, 4H), 1.72(s, 6H) 111

MS (ESI) m/z 513.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.20 (bs,1H), 9.08 (d, J = 0.6 Hz, 1H), 8.54 (d, J = 0.64 Hz, 1H), 8.30 (s, 1H),7.78 (d, J = 2.24 Hz, 1H), 7.59 (dd, J = 8.44, 2.28 Hz, 1H), 7.41-7.38(m, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.21-7.19 (m, 2H), 7.18 (t, J = 67.48Hz, 1H), 4.35 (s, 4H). 112

MS (ESI) m/z 525.31 [M + 1]+; 1H NMR (400 mHz, DMSO-d6) δ 13.50 (s, 1H),9.02 (s, 1H), 8.47 (s, 1H), 8.30 (t, J = 1.6 Hz, 1H), 8.18 (s, 1H), 8.13(s, 2H), 7.50-7.48 (m, 1H), 7.46 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H),4.39-4.38 (m, 2H), 4.33-4.32 (m, 2H), 3.32 (s, 3H) 113

MS (ESI) m/z 531.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H),8.57 (s, 1H), 8.54 (bs, 1H), 7.74 (bs, 1H), 7.37-7.32 (m, 2H), 7.30 (d,J = 2.52 Hz, 1H), 7.16 (d, J = 8.88 Hz, 1H), 7.09 (d, J = 8.04 Hz, 1H),4.39 (t, J = 4.76 Hz, 2H), 4.34 (t, J = 4.68 Hz, 2H) 114

MS (ESI) m/z 492.36 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.58 (bs,1H), 9.07 (s, 1H), 8.55 (s, 1H), 8.35 (s, 1H), 7.32 (d, J = 7.16 Hz,1H), 7.22 (s, 1H), 7.12 (d, J = 8.88 Hz, 1H), 6.92 (s, 1H), 6.87 (s,1H), 5.10 (bs, 2H), 4.38 (bs, 2H), 4.30 (bs, 2H), 3.76 (s, 3H) 115

MS (ESI) m/z 462.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H),8.56 (s, 1H), 8.19 (d, J = 3.72 Hz, 1H), 8.12 (s, 1H), 7.41 (dd, J =8.8, 2.8 Hz, 1H), 7.23 (bs, 1H), 7.16-7.14 (m, 2H), 4.28 (bs, 4H), 2.03(s, 3H) 116

MS (ESI) m/z 487.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H),8.54 (s, 1H), 8.11 (s, 1H), 7.68 (bs, 1H), 7.51 (dd, J = 8.8, 2.4 Hz,1H), 7.31 (d, J = 2.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.33 (s, 4H),2.50 (s, 3H) 117

MS (ESI) m/z 487.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.27 (bs,1H), 11.92 (s, 1H), 8.91 (s, 1H), 8.40 (bs, 1H), 8.37 (s, 1H), 7.99 (s,1H), 7.74 (d, J = 2.64 Hz, 1H), 7.68 (t, J = 2.84 Hz, 1H), 7.42 (dd, J =8.88, 2.8 Hz, 1H), 7.26 (d, J = 8.76 Hz, 1H), 6.84 (t, J = 1.96 Hz, 1H),4.47 (t, J = 4.72 Hz, 2H), 4.38 (t, J = 4.64 Hz, 2H) 118

MS (ESI) m/z 498.41 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H),8.56 (d, J = 8.56 Hz, 1H), 8.40 (s, 1H), 8.02 (d, J = 5.72 Hz, 1H), 7.70(t, J = 7.08 Hz, 1H), 7.62-7.60 (m, 2H), 7.54 (dd, J = 8.76, 2.64 Hz,1H), 7.29-7.26 (m, 2H), 7.18 (d, J = 5.64 Hz, 1H), 4.33-4.23 (m, 2H),4.17-4.09 (m, 2H) 119

MS (ESI) m/z 601.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.92 (bs,1H), 8.83 (d, J = 4.64 Hz, 1H), 8.38 (s, 1H), 7.87 (s, 1H), 7.59 (dd, J= 8.76, 2.24 Hz, 1H), 7.51 (t, J = 52.0 Hz, 1H), 7.49 (d, J = 4.68 Hz,1H), 7.43 (d, J = 2.28 Hz, 1H), 7.35 (d, J = 8.96 Hz, 1H), 4.39 (t, J =5.56 Hz, 2H). 4.23 (t, J = 4.92 Hz, 2H), 1.73 (s, 3H) 123

MS (ESI) m/z 599.53 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.92 Hz, 1H), 8.08 (d, J = 9.72 Hz, 1H), 7.60 (dd, J = 8.88, 2.64 Hz,1H), 7.53 (d, J = 4.96 Hz, 1H), 7.41 (d, J = 2.56 Hz, 1H), 7.38 (t, J =64.56 Hz, 1H), 7.35 (d, J = 1.72 Hz, 1H), 4.44 (t, J = 5.40 Hz, 2H),4.23 (t, J = 4.84 Hz, 2H), 2.49 (s, 3H), 1.96 (s, 3H) 124

UPLC: MS (ESI) m/z 443.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s,1H), 8.51 (s, 1H), 8.41 (s, 1H), 7.94 (s, 1H), 7.73 (d, J = 7.52 Hz,1H), 7.41 (d, J = 7.68 Hz, 1H), 7.25 (t, J = 7.52 Hz, 1H), 7.06 (d, J =8.76 Hz, 1H), 6.88-6.85(dd, J = 2.84 Hz, J = 2.72 Hz, 1H), 6.82 (d, J =2.92 Hz, 1H), 4.34 (t, J = 4.6 Hz, J = 4.88 Hz 2H), 4.23 (d, J = 4.48Hz), 3.72 (s, 3H) 125

UPLC: MS (ESI) m/z 429.28 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.20(bs, 1H), 9.10 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 7.87 (s, 1H), 7.69(d, J = 7.68 Hz, 1H), 7.42 (d, J = 7.76 Hz, 1H), 7.25 (t, J = 7.64 Hz,1H), 6.96 (d, J = 8.68 Hz, 1H), 6.71-6.68 (dd, J = 2.96 Hz, J = 2.92 Hz,1H), 6.65 (d, J = 2.8 Hz, 1H), 4.30 (t, J = 4.8 Hz, 2H), 4.17 (t, J =4.88 Hz, 2H) 126

MS (ESI) m/z 463.36 [M + 1]+; UPLC: 99.75%; 1H NMR (400 MHz, DMSO-d6) δ13.01 (s, 1H), 9.10 (s, 1H), 8.53 (s, 1H), 8.29 (s, 1H), 7.89 (s, 1H),7.86 (d, J = 7.76 Hz, 1H), 7.58 (t, J = 8.20 Hz, 2H), 7.48 (s, 1H), 7.44(t, J = 7.68 Hz, 1H) 7.30 (d, J = 8.60 Hz, 1H), 7.14-6.86 (m, 1H),4.42-4.38 (m, 4H) 127

MS (ESI) m/z 471.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.94 (bs,1H), 9.10 (s, 1H), 8.51 (s, 1H), 7.99 (s, 1H), 7.78 (dd, J = 7.56, 11.2Hz, 1H), 7.43-7.34 (m, 3H), 7.17-7.15 (m, 2H), 4.28 (s, 4H), 3.80 (s,1H) 128

MS (ESI) m/z 471.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 16.5 (bs, 1H),8.92 (s, 1H), 8.47(s, 1H), 8.23 (s, 1H), 7.97 (d, J = 1.48 Hz,2H),7.55-7.51 (m, 2H), 7.43 (dd, J = 2.56 Hz, J = 2.68 Hz 1H), 7.39 (d,J = 2.6 Hz, 1H), 7.23 (d, J = 8.76 Hz, 1H), 4.36 (s, 4H) 129

MS (ESI) m/z 461.21 [M + 1]+. UPLC: 99.41%; 1H NMR (400 MHz, DMSO-d6) δ12.88 (s, 1H), 9.02 (s, 1H), 8.45 (s, 1H), 8.40 (s, 1H), 7.75 (s, 1H),7.57 (d, J = 7.76 Hz, 1H), 7.44-7.38 (m, 2H), 7.29 (d, J = 2.60 Hz, 1H),7.23 (d, J = 8.88 Hz, 1H) 7.16 (t, J = 7.72 Hz, 1H), 5.14- 5.09 (m, 1H),4.53-4.49 (m, 1H), 4.42- 4.37 (m, 1H), 1.43 (d, J = 6.96 Hz, 3H) 130

MS (ESI) m/z 439.10 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 12.83 (bs,1H), 9.17 (s, 1H), 8.56 (d, J = 8.44 Hz, 2H), 7.96 (s, 1H), 7.71-7.68(m, 2H), 7.62 (d, J = 8.36 Hz, 1H), 7.53 (d, J = 2.04 Hz, 1H), 7.51-7.58(dd, J = 2.08 Hz, J = 2.20 Hz, 1H), 7.37 (t, J = 7.68 Hz, 1H), 4.91 (s,2H) 131

MS (ESI) m/z 479.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.03 (bs,1H), 10.82 (s, 1H), 8.79 (s, 1H), 8.62 (s, 1H), 7.98 (s, 1H), 7.95 (s,1H), 7.87 (d, J = 7.76 Hz, 1H), 7.58 (d, J = 7.56 Hz, 1H), 7.42-7.38 (m,2H), 7.34 (d, J = 2.76 Hz, 1H), 7.19 (d, J = 8.92 Hz, 1H), 4.32 (s, 4H),2.13 (s, 3H) 132

MS (ESI) m/z 479.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H),8.90 (d, J = 4.8 Hz, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.86(d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.43-7.38 (m, 2H), 7.34(d, J = 2.4 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 4.35 (s, 4H), 2.93 (s,3H) 133

MS (ESI) m/z 514 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H),8.29 (d, J = 8.72 Hz, 1H), 8.19 (s, 1H), 8.07 (d, J = 8.64 Hz, 1H), 7.88(s, 1H), 7.83 (d, J = 7.76 Hz ,1H), 7.60 (d, J = 7.76 Hz ,1H), 7.38-7.42(m, J = 8.32 Hz, 2H), 7.33 (d, J = 2.68 Hz, 1H), 7.22 (d, J = 8.8 Hz,1H), 4.3 (s, 4H) 134

MS (ESI) m/z 462 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.9 (b, 1H),9.04 (s, 1H), 8.63 (d, J = 4.96 Hz, 1H), 8.48 (s, 1H), 7.915 (s, 1H),7.56 (dd, J = 1.52 Hz, J = 4.96Hz, 1H), 7.484 (dd, J = 1.68, 8.92 Hz,1H), 7.40 (d, J = 2.6 Hz, 1H), 7.24 (d, J = 8.92 Hz, 1H), 4.385 (s, 4H),2.278 (s, 3H) 135

UPLC: MS (ESI) m/z 518.43 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s,1H), 8.84 (d, J = 4.8 Hz, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 7.60-7.57(dd, J = 2.6 Hz, J = 2.6 Hz, 1H), 7.47 (d, J = 4.76 Hz, 1H), 7.43 (d, J= 2.6 Hz, 1H), 7.33 (d, J = 8.96 Hz, 1H), 4.38 (t, J = 4.8 Hz, 2H), 4.25(t, J = 4.76, 5.0 Hz, 2H), 1.81 (s, 3H) 136

MS (ESI) m/z 488.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.96 (bs,1H), 8.93 (s, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.928-7.86(m, 3H), 7.61 (d, J = 7.2 Hz, 1H), 7.45-7.39 (m, 2H), 7.341 (s, 1H),7.21 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H), 4.35 (s, 4H) 137

MS (ESI) m/z 493.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H),8.92 (s, 1H), 8.08 (s, 1H), 8.04 (d, J = 4.32 Hz, 1H), 7.93 (s, 1H),7.89 (s, 1H), 7.86 (s, 1H), 7.56 (d, J = 6.88 Hz, 1H), 7.40-7.36 (m,2H), 7.33 (d, J = 2.56 Hz, 1H), 7.20 (d, J = 8.84 Hz, 1H), 4.328 (s,4H), 3.75 (s, 2H), 2.59 (d, J = 4.6 Hz, 3H) 138

MS (ESI) m/z 436.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s,1H),8.89 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.86 (d, J = 7.72 Hz, 1H),7.76 (s, 1H),7.57 (d, J = 1.28 Hz, 1H), 7.409-7.37 (m, 2H), 7.333-7.326(m, 2H), 7.20 (d, J = 8.88 Hz, 1H), 4.34 (s, 4H), 2.607 (s, 3H). 139

MS (ESI) m/z 496.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.927 (bs,1H), 8.187 (s, 1H), 8.158 (s, 1H), 8.079 (s, 1H), 7.91 (s, 1H), 7.83 (d,J = 7.8 Hz, 1H), 7.599 (d, J = 7.96 Hz, 1H), 7.419-7.08 (m, 5H), 4.349(s, 4H) 141

MS (ESI) m/z 494.34 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.931 (bs,1H), 8.061(d, J = 8.88 Hz, 1H), 7.875-7.82 (m, 3H), 7.517 (d, J = 7.4Hz, 1H), 7.425- 7.386 (m, 2H), 7.276 (d, J = 2.28 Hz, 1H), 7.205 (d, J =8.8 Hz, 1H), 4.343 (s, 4H), 2.173 (s, 3H) 142

MS (ESI) m/z 528.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.9 (s, 1H),8.28 (d, J = 7.92 Hz, 1H), 8.08 (d, J = 7.84 Hz, 1H), 7.92 (s, 1H), 7.85(d, J = 7.76 Hz, 1H), 7.53 (d, J = 7.76 Hz ,1H), 7.33-7.41 (m, 2H), 7.28(d, J = 4.4 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 4.3 (s, 4H), 2.24 (s, 3H)143

MS (ESI) m/z 553.44 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H),8.42 (s, 1H), 8.12 (d, J = 6.84 Hz, 1H), 7.99 (t, J = 6.8 Hz, 1H), 7.89(d, J = 7.28 Hz, 1H), 7.72 (d, J = 4.16 Hz, 1H), 7.47- 7.44 (m, 2H),7.37 (d, J = 8.08 Hz, 1H), 6.59 (t, J = 51.6 Hz, 1 H), 4.41(s, 2H), 4.34(s, 2H) 144

MS (ESI) m/z 662.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6): δ 12.63 (s,1H), 8.86 (d, J = 4.8 Hz, 1H), 8.54 (s, 1H), 8.06 (d, J = 9.8 Hz, 1H),7.63-7.60 (dd, J = 2.5, 2.6 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.42-7.36(m, 3H), 4.44 (t, J = 6.1 Hz, 2H), 4.28 (t, J = 5.8 Hz, 2H), 3.53 (s,3H), 1.90 (s, 3H) 148

MS (ESI) m/z 540.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.10 (bs,1H), 8.15-8.13 (m, 1H), 8.07-8.00 (m, 2H), 7.70 (d, J = 1.3 Hz, 1H),7.63-7.58 (m, 2H), 7.44-7.42 (dd, J = 2.6, 8.7 Hz, 1H), 7.39 (d, J = 2.6Hz, 1H), 7.2 (d, J = 8.9 Hz, 1H), 7.08-6.82 (t, J = 51.9 Hz, 1H), 4.43(t, J = 6.1 Hz, 2H), 4.34 (t, J = 5.5 Hz, 2H) 153

MS (ESI) m/z 510.40 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.94 (bs,1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.89-7.84 (m, 2H), 7.53 (d, J = 7.6 Hz,1H), 7.41-7.20 (m, 5H), 4.35 (m, 4H), 2.20 (s, 3H) 154

MS (ESI) m/z 528.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H),7.87 (d, J = 7.72 Hz, 1H), 7.81 (s, 1H), 7.54 (d, J = 7.88 Hz, 1H), 7.45(m, 2H), 7.27 (d, J = 4 Hz, 1H), 7.27 (d, J = 8 Hz, 1H),4.39 (m, 4H),2.21 (s, 3H) 160

MS (ESI) m/z 567.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.76 Hz, 1H), 8.40 (s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 8.52Hz, 1H), 7.59 (dd, J = 2.4, 8.92 Hz, 1H), 7.50-7.23 (m, 4H), 4.42-4.23(m, 4H), 1.79 (s, 3H) 161

MS (ESI) m/z 497.87 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J =4.92 Hz, 1H), 8.20 (s, 1H), 8.163 (d, J = 8.6, 1H), 8.0474 (t, J = 8.4Hz 2H), 7.67 (dd, J = 1.4, 6.4 Hz, 1H), 7.65 (m, 4H), 4.39 (m, 4H) 163

MS (ESI) m/z 521.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.40 (b, 1H),8.49 (d, J = 4.84 Hz, 1H), 8.14 (d, J = 6.28 Hz, 1H), 8.07- 8.02 (m,2H), 7.49 (m, 1H), 7.43 (d, J = 4.88 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H),7.23 (d, J = 8.92 Hz, 1H), 6.71 (t, J = 52.2 Hz, 1H) 4.38-4.33 (m, 4H),4.19 (s, 1H) 165

MS (ESI) m/z 520.17 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.91 (bs,1H), 8.12 (d, J = 6.68 Hz, 1H), 8.04-7.98 (m, 2H), 7.78-7.76 (m, 1H),7.42-7.37 (m, 3H), 7.20-7.07 (m, 2H), 6.68- 6.42 (t, J = 52.32 Hz, 1H),4.36-4.30 (m, 4H), 3.90 (s, 1H) 166

MS (ESI) m/z 497.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H),8.15 (d, J = 5.56 Hz, 1H), 8.07-7.99 (m, 3H), 7.645 (s, 1H), 7.51- 7.46(m, 2H), 7.23 (d, J = 8.92 Hz, 1H), 7.04- 6.78 (m, 2H), 4.44-4.38 (m,4H) 167

MS (ESI) m/z 478.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.912 (bs,1H), 8.028 (d, J = 8.84 Hz, 1H), 7.879 (d, J = 7.72 Hz, 2H), 7.813 (s,1H), 7.696 (d, J = 9.36 Hz, 1H), 7.52 (d, J = 7.48 Hz, 1H), 7.449-7.394(m, 2H), 7.283 (s, 1H), 7.2079 (d, J = 8.8 Hz, 1H), 4.334 (m, 4H), 2.163(s, 3H) 170

MS (ESI) m/z 421.2 [M + 1]+; 1H NMR (500 MHz, DMSO-d6) δ 13.01 (bs, 1H),12.21 (bs, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.94 (d, J = 7.5 Hz, 1H),7.62-7.61 (m, 1H), 7.55-7.50 (m, 3H), 7.35-7.34 (m, 2H), 7.20-7.17 (m,2H), 4.27 (t, J = 6.5 Hz, 2H), 3.62 (t, J = 6.5 Hz, 2H) 171

MS (ESI) m/z 468.2 [M + 1]+; 1H NMR (300 MHz, DMSO-d6) δ 8.03 (s, 1H),7.93 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.54-7.49 (m, 1H),7.37-7.34 (m, 2H), 7.27-7.16 (m, 2H), 6.78-6.73 (m, 1H), 4.20 (t, J =6.5 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 2.87 (d, J = 3.3 Hz, 3H) 172

MS (ESI) m/z 486.2 [M + 1]+. 1H NMR (300 MHz, DMSO-d6) δ 13.00 (bs, 1H),11.10 (bs, 1H), 8.04 (s, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 7.8Hz, 1H), 7.51-7.46 (m, 1H), 7.38-7.34 (m, 2H), 7.18 (d, J = 8.4 Hz, 2H),6.75-6.68 (m, 1H), 6.43 (bs, 1H), 4.24-4.20 (m, 2H), 3.49-3.46 (m, 2H),2.84 (d, J = 4.8 Hz, 3H) 173

MS (ESI) m/z 563.4 [M + 1]+; 1H NMR (300 MHz, DMSO-d6) δ 12.16 (bs, 1H),10.34 (bs, 1H), 8.13 (s, 1H), 7.31 (s, 1H), 7.21 (s, 1H), 7.19 (d, J =7.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 2H), 6.76-6.75 (m, 1H), 6.68-6.54 (m,5H), 6.37 (d, J = 8.1 Hz, 1H), 6.29-6.24 (m, 1H), 3.48 (t, J = 6.6 Hz,2H), 2.74 (t, J = 6.3 Hz, 2H) 174

MS (ESI) m/z 555.31 [M + 1]+; UPLC: 97.62%; 1H NMR (400 MHz, DMSO-d6) δ13.00 (bs, 1H), 10.97 (bs, 1H), 9.04 (s, 1H), 8.01 (s, 1H), 7.92 (d, J =7.76 Hz, 1H), 7.82 (d, J = 7.92 Hz, 2H), 7.60 (d, J = 7.60 Hz, 1H), 7.45(t, J = 7.68 Hz, 1H), 7.39-7.33 (m, 4H), 7.18 (d, J = 8.84 Hz, 1H),7.12-7.07 (m, 1H), 6.86 (d, J = 10.32 Hz, 1H), 4.30 (t, J = 5.96 Hz,2H), 3.59 (t, J = 5.84 Hz, 2H 175

MS (ESI) m/z 583.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.68 (bs,1H), 8.90 (s, 1H), 8.79 (d, J = 4.96 Hz, 1H), 8.57 (s, 1H), 7.66 (d, J =7.72 Hz, 2H), 7.57-7.60 (dd, J = 2.68 Hz, J = 2.56 Hz, 1H), 7.52 (d, J =2.56 Hz, 1H), 7.43 (s, 1H), 7.37-7.32 (m, 4H), 7.01-7.07 (m 1H), 4.51(d, J = 4.72 Hz, 2H), 4.23 (t, J = 4.56 Hz, 2H) 176

MS (ESI) m/z 513.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.0 (bs, 1H),11.02 (bs, 1H), 8.91 (s, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.93 (d, J =7.6 Hz, 1H), 7.74 (d, J = 7.16 Hz, 2H), 7.60 (d, J = 7.44 Hz, 1H), 7.50(t, J = 7.56 Hz, 1H), 7.38-7.34 (m, 4H), 7.19 (d, J = 8.80 Hz, 1H), 7.07(t, J = 7.32 Hz, 1H), 6.88 (s, 1H), 4.30 (t, J = 6.0 Hz, 2H), 3.56 (d, J= 5.72 Hz, 2H) 177

MS (ESI m/z 544.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H),11.73 (s, 1H), 8.07 (s, 1H), 7.999-7.995 (t, J = 1.64 Hz, 1H), 7.94-7.91(td, J = 9.08, J = 1.36 Hz, 1H), 7.56-7.53 (td, J = 7.80, J = 1.64 Hz,1H), 7.47-7.44 (t, J = 7.68 Hz, 1H), 7.39-7.34 (m, 3H), 7.16 (d, J =8.88 Hz, 1H), 4.33-4.24 (m, 4H), 3.56-3.53 (t, J = 6.0, 2H) 178

LCMS (ESI) m/z 581.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.94 (bs,1H), 11.10 (bs, 1H), 8.91 (s, 1H), 8.06 (s, 1H), 7.90 (d, J = 6.0 Hz,1H), 7.71 (d, J = 5.7 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.45 (t, J =6.0 Hz, 1H), 7.41-7.34 (m, 5H) 7.26 (s, 1H), 7.19 (d. J = 6.8 Hz, 1H),7.11 (t, J = 6.0 Hz, 1H), 4.35 (m, 2H), 3.68 (m, 2 H) 179

MS (ESI) m/z 538.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.99 (b, 1H),11.20 (s, 1H), 9.09 (s, 1H), 8.11 (s, 1H), 8.00-8.01 (m, 1H), 7.94- 7.91(m, 1H), 7.84 (d, J = 8 Hz, 2H), 7.58-7.55 (m, 1H), 7.48 (t, J = 8 Hz,1H), 7.40-7.34 (m, 4H), 7.18 (d, J = 9 Hz, 1H), 7.13-7.09 (m, 1H), 4.31(t, J = 6 Hz, 2H), 3.57 (t, J = 6 Hz, 2H) 180

MS (ESI) m/z 598.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.51 (s, 1H), 8.27-8.26 (m, 1H), 8.16 (dd, J = 1.5, 0.6 Hz,1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.41 (d,J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.23 (t, J = 6.1 Hz, 2H),3.62 (s, 3H), 2.89 (t, J = 6.1 Hz, 2H), 1.85 (s, 3H) 188

MS (ESI) m/z 603.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80-8.74 (m,1H), 8.44-8.42 (m, 1H), 8.22 (d, J = 8.8, 1H), 8.02 (d, J = 8.8 HZ, 1H),7.65-7.58 (m, 1H), 7.55-7.28 (m, 4H), 6.73-6.42 (m, 1H), 4.42(s, 2H),4.34 (s, 2H) 189

MS (ESI) m/z 553.14 [M + 1]+; UPLC: 98.14%; 1H NMR (400 MHz, DMSO-d6) δ13.149 (s, 1H), 8.54 (d, J = 5.48, 1H), 8.21 (d, J = 5.2 Hz, 1H), 8.174(s, 1H), 8.13 (d, J = 7.32 Hz, 1H), 7.96-8.00 (t, J = 7.64 Hz, 1H), 7.91(d, J = 8.12 Hz, 1H), 7.59-7.56 (dd, J = 2.6, 8.84 Hz, 1H), 7.36-7.33(m, 2H), 6.63-6.37 (t, J = 52.08 Hz, 1H), 4.40 (d, J = 4.68, 2H), 4.32(d, J = 4.68, 2H) 190

MS (ESI) m/z 553.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.61 (m, 1H),9.29 (s, 1H), 8.11-8.07 (t, J = 7.48 Hz, 2H), 8.04-8.00 (t, J = 7.52 Hz,1H), 7.93 (d, J = 8.2 Hz, 1H), 7.60-7.55 (m, 2H), 7.41 (d, J = 2.52 Hz,1H), 7.54 (d, J = 8.96 Hz, 1H), 6.68-6.43 (t, J = 51.88 Hz, 1H), 4.40(d, J = 4.76, 2H), 4.33 (d, J = 4.64, 2H) 191

MS (ESI) m/z 550.33 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H),8.10 (d, J = 7.56 Hz, 1H), 8.005 (t, J = 8.38 Hz, 2H), 7.93 (t, J = 4.28Hz, 2H), 7.55-7.52 (m, 1H), 7.49 (d, J = 5.6 Hz, 1H), 7.34 (t, J = 3.96Hz, 1H), 7.30 (d, J = 5.52, 1H), 7.27 (s, 1H), 6.44 (t, J = 5.2 Hz, 1H),4.35 (t, J = 5.52 Hz, 2H), 4.28 (t, J = 4.42 Hz, 2H) 192

MS (ESI) m/z 542.2 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H),8.16-8.14 (m, 1H), 8.09-8.03 (m, 2H), 7.76 (s, 1H), 7.39-7.36 (dd, J =2.60, 2.64 Hz, 1H), 7.13 (d, J = 8.84 Hz ,1H), 7.06 (d, J = 2.6 Hz, 1H),6.91 (s, 1H), 4.72-4.64 (m, 2H), 4.39 (s, 2H), 4.29 (s, 2H) 193

MS (ESI) m/z 542.2 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H),8.16-8.14 (m, 1H), 8.09-8.03 (m, 2H), 7.76 (s, 1H), 7.39-7.36 (dd, J =2.60, 2.64 Hz, 1H), 7.13 (d, J = 8.84 Hz ,1H), 7.06 (d, J = 2.6 Hz, 1H),6.91 (s, 1H), 4.72-4.64 (m, 2H), 4.39 (s, 2H), 4.29 (s, 2H) 194

MS (ESI) m/z 595.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.5 Hz, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 7.59 (d, J = 8.8Hz, 1H), 7.48 (d, J = 4.7 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 9.1 Hz,1H), 4.41 (t, J = 4.0 Hz, 2H), 4.24 (t, J = 5.5 Hz, 2H), 1.74 (s, 3H)195

MS (ESI) m/z 595.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.7 Hz, 1H), 8.417 (s, 1H), 8.35 (d, J = 8.72 Hz, 1H), 7.87 (d, J =8.76, 1H), 7.60 (dd, J = 8.8 Hz 2.44 Hz, 1H), 7.48 (d, J = 4.68 Hz, 1H),7.43 (d, J = 2.44 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.405 (d, J = 4.1Hz, 2H), 4.269 (s, 2H), 3.539 (s, 3H), 1.83 (s, 3H) 196

MS (ESI) m/z 624.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.43 (s, 1H), 8.26 (d, J = 8.76 Hz, 1H), 7.82 (d, J = 8.76,1H), 7.60 (dd, J = 8.8 Hz, 2.64 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.46(d, J = 2.6 Hz, 1H), 7.36 (d, J = 8.96 Hz, 1H), 4.41(t, J = 4.48 Hz,2H), 4.25 (t, J = 4.68 Hz, 2H), 2.85 (s, 6H). 1.76 (s, 3H) 197

MS (ESI) m/z 592.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.76 Hz, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 7.61 (dd, J = 2.44, 8.96 Hz,1H), 7.51-7.24 (m, 4H), 4.43 (s, 2H), 4.31 (s, 2H), 1.98 (s, 3H) 198

MS (ESI) m/z 592.01 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.84 Hz, 1H), 8.39 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.61-7.58 (dd, J= 2.52 Hz, 6.36 Hz, 1H), 7.53 (d, J = 4.80 Hz, 1H), 7.44 (d, J = 2.56Hz, 1H), 7.354 (d, J = 9.00 Hz, 1H), 4.38-4.36 (m, 2H), 4.20-4.18 (m,2H), 1.74 (s, 3H) 200

MS (ESI) m/z 551.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.76 Hz, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.59(dd, J = 8.8, 2.3 Hz, 1H), 7.49 (d, J = 4.7 Hz, 1H), 7.43 (d, J = 2.3Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 4.39 (t, J = 4.4 Hz, 2H), 4.22 (t, J= 5.7 Hz, 2H), 1.74 (s, 3H) 204

MS (ESI) m/z 595.21 [M + 1]+; UPLC: 99.31%; 1H NMR (400 MHz, DMSO-d6) δ9.25 (s, 1H), 9.10 (s, 2H), 8.75 (d, J = 4.8 Hz, 1H), 8.55 (s, 1H),8.10-8.03 (q, 2H), 7.61-7.58 (dd, J = 2.6 Hz, 2.6 Hz 1H), 7.49 (d, J =4.76 Hz, 1H), 7.44 (d, J = 8.12, 1H), 7.38 (d, J = 8.92 Hz, 1H), 4.46(t, J = 4.84 Hz, 2H), 4.28 (t, J = 6.44 Hz, 2H), 1.93 (s, 3H) 207

MS (ESI) m/z 585.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.31 (bs,1H), 8.83 (d, J = 4.7 Hz, 1H), 8.36 (s, 1H), 7.92 (s, 1H), 7.59 (dd, J =8.8, 2.5 Hz, 1H), 7.47 (d, J = 4.7 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H),7.35 (d, J = 8.8 Hz, 1H), 4.39 (t, J = 5.6 Hz, 2H), 4.23 (t, J = 4.8 Hz,2H), 1.72 (s, 3H) 208

MS (ESI) m/z 594.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.33 (bs,1H), 8.83 (d, J = 4.6 Hz, 1H), 8.44 (s, 1H), 7.61-7.57 (m, 2H),7.47-7.42 (m, 2H), 7.33 (d, J = 8.5 Hz, 1H), 4.35 (bs, 2H), 4.17 (bs,2H), 1.71 (s, 3H) 209

MS (ESI) m/z 585.06 [M + 1]+; UPLC: 99.28%; 1H NMR (400 MHz, DMSO-d6) δ13.20 (s, 1H), 8.80 (d, J = 4.72 Hz, 1H), 8.54 (s, 1H), 8.39 (s, 1H),7.60-7.58 (dd, J = 2.32, 2.24 Hz, 1H), 7.45-7.42 (dd, J = 4.76, 2.64 Hz,2H), 7.36 (d, J = 8.92 Hz, 1H), 4.38 (s, 2H), 4.23 (s, 2H), 1.86 (s,3H). 211

MS (ESI) m/z 541.16 [M + 1]+; UPLC: 99.9%; 1H NMR (400 MHz, DMSO-d6) δ8.81 (d, J = 4.80 Hz, 1H), 8.65 (s, 1H), 8.05 (d, J = 7.76 1H), 7.89 (d,J = 7.72, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 2.44 Hz, 2H), 7.36(d, J = 9 Hz, 1H), 4.75 (s, 1H), 4.40 (s, 2H), 4.26 (s, 2H), 1.93 (s,3H) 212

MS (ESI) m/z 542.12 [M + 1]+; UPLC: 99.61%; 1H NMR (400 MHz, DMSO-d6) δ13.34 (bs, 1H), 8.83 (d, J = 4.56 Hz, 1H), 8.47(s, 1H), 8.32 (s, 1H),8.15 (s,1H), 7.60-7.57 (dd, J = 3.52, 1.72 Hz, 1H), 7.46 (d, J = 4.60Hz, 1H), 7.42 (d, J = 2.32 Hz, 1H), 7.34 (d, J = 8.96 Hz, 1H), 4.41-4.39 (t, J = 5.28 Hz, 2H), 4.25-4.22 (t, J = 5.04 Hz, 2H), 1.77 (s, 3H)213

MS (ESI) m/z 541.16 [M + 1]+; UPLC: 99.87%; 1H NMR (400 MHz, DMSO-d6) δ13.34 (bs, 1H), 8.83 (d, J = 4.84 Hz, 1H), 8.38 (s, 1H), 8.02 (s, 1H),7.74 (s, 1H), 7.60-7.57 (dd, J = 8.84, 2.36 Hz, 1H), 7.47-7.43 (dd, J =11.20, 4.8 Hz, 2H), 7.34 (d, J = 8.92 Hz, 1H), 4.71 (s, 1H), 4.38 (s,2H), 4.21 (s, 2H), 1.72 (s, 3H) 216

MS (ESI) m/z 644.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83-8.79 (m,3H), 8.29 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.84 (d, J = 5.68 Hz,2H), 7.59 (dd, J = 2.56, J = 8.84 Hz, 1H), 7.51 (d, J = 4.8 Hz, 1H),7.44 (d, J = 2.60 Hz, 1H), 7.34 (d, J = 8.96 Hz, 1H) 4.38 (t, J = 5.76Hz, 2H), 4.22 (t, J = 4.60 Hz, 2H), 1.69 (s, 3H) 217

MS (ESI) m/z 581.08 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 13.39 (bs,1H), 8.84 (d, J = 4.4 Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.81 (s, 1H),7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.43 (d, J =2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 4.40 (t, J = 5.9 Hz, 2H), 4.23(t, J = 4.8 Hz, 2H), 2.14 (t, J = 19.6 Hz, 3H), 1.72 (s, 3H) 218

MS (ESI) m/z 618.02 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 13.2 (s, 1H),8.85-8.84 (d, J = 4.0 Hz, 1H), 8.47 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H),7.59-7.58 (d, J = 4.0 Hz, 1H), 7.51-7.50 (d, J = 4.0 Hz, 1H), 7.39-7.38(m, 2H), 4.46-4. (bs, 2H), 4.31 (bs, 2H), 1.76 (s, 3H) 219

MS (ESI) m/z 628.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.65 (bs,1H), 8.83 (d, J = 4.76 Hz, 1H), 8.31 (s, 1H), 8.03 (d, J = 3.84 Hz, 2H),7.60-7.57 (dd, J = 2.4 Hz 6.36 Hz, 1H), 7.48 (d, J = 4.72 Hz, 1H), 7.43(d, J = 2.44 Hz, 1H), 7.35 (d, J = 8.96 Hz, 1H), 4.38-4.35 (m, 2H),4.25-4.22 (m, 2H), 1.77 (s, 3H) 220

MS (ESI) m/z 610.05 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 13.2 (s, 1H),8.83-8.82 (d, J = 4, 1H), 8.20 (s, 1H), 7.93-7.87 (m, 2H), 7.60-7.57 (m,1H), 7.46-7.42 (m, 2H), 7.35-7.33 (d, J = 8 Hz, 1H), 4.36-4.38 (t, J = 4Hz, 2H), 4.25-4.24 (t, J = 4 Hz, 2H), 1.78 (s, 3H) 221

MS (ESI) m/z 592.03 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.41 (s, 1H), 7.81 (s, 1H), 7.60- 7.57 (dd, J = 8.0, 2.52Hz, 1H), 7.49 (d, J = 4.7 Hz, 1H), 7.44 (d, J = 2.52 Hz, 1H), 7.37-7.33(m, 2H), 5.90 (s, 1H), 4.36- 4.34 (t, J = 7.52 Hz, 2H), 4.18-4.15 (t, J= 7.96 Hz, 2H), 1.7 (s, 3H) 222

MS (ESI) m/z 607.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.84 Hz, 1H), 8.39 (s, 1H), 7.60-7.57 (m, 1H), 7.49 (d, J = 4.84 Hz,1H), 7.43 (d, J = 2.6 Hz, 1H), 7.39 (s, 1H), 7.35 (s, 1H), 7.25 (s, 1H),4.35-4.34 (t, J = 4.72 Hz, 2H),4.20-4.18 (t, J = 4.32 Hz, 2H), 2.46 (s,3H), 1.75(s, 3H) 223

MS (ESI) m/z 638.04 [M + 1]. 1H NMR (400 MHz, DMSO-d6) δ 13.2 (s, 1H),8.83 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.59-7.57 (d, J= 8 Hz, 1H), 7.43 (d, J = 12 Hz, 2H), 7.34 (d, J = 8 Hz, 1H), 4.43-4.41(t, J = 4.0 Hz, 2H), 4.31- 4.29(t, J = 4.0 Hz, 2H), 3.61(s, 3H), 1.93(s, 3H) 224

MS (ESI) m/z 599.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.3 (s, 1H),8.83 (d, J = 4 Hz, 1H), 8.66 (s, 1H), 8.36 (s, 1H), 8.32 (s, 1H),7.60-7.58 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 4.0 Hz, 1H), 7.40 (s, 1H),7.35 (d, J = 12 Hz, 1H), 4.42- 4.40 (t, J = 4.0 Hz, 2H), 4.28-4.26 (t, J= 5.6 Hz, 2H), 1.82 (s, 3H) 228

MS (ESI) m/z 540.16 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.35 (t, J = 4.18 Hz, 2H), 7.78 (d, J = 8.6 Hz, 1H),7.61-7.58 (dd, J = 2.56, 2.56 Hz, 1H), 7.49 (d, J = 4.72 Hz, 1H), 7.42(d, J = 2.56 Hz, 1H), 7.36 (d, J = 8.96 Hz, 1H), 4.40 (d, J = 4.64 Hz,2H), 4.26 (d, J = 4.32 Hz, 2H), 1.79 (s, 3H) 229

MS (ESI) m/z 595.18 [M + 1]+; UPLC: 99.8%; 1H NMR (400 MHz, DMSO-d6) δ8.83 (d, J = 4.80 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J = 7.92, 1H), 8.10(d, J = 7.88, 1H), 7.59 (dd, J = 2.04, 3.76 Hz, 1H), 7.44-7.47 (m, 2H),7.37 (d, J = 8.92 Hz, 1H), 4.34 (s, 2H), 4.29 (s, 2H), 3.62 (s, 3H),2.061 (s, 3H) 230

MS (ESI) m/z 585.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.19 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 7.64-7.54 (m, 2H),7.48-7.28 (m, 4H), 4.40 (t, J = 5.7 Hz, 2H), 4.24 (t, J = 5.2 Hz, 2H),1.76 (s, 3H) 231

MS (ESI) m/z 503.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H),8.54 (s, 1H), 7.88 (d, J = 7.24 Hz, 1H), 7.81 (s, 1H), 7.48 (d, J = 7.16Hz, 1H), 7.39 (m, 2H), 7.26 (s, 1H), 5.08 (d, J = 45.84 Hz, 2H), 4.31(s, 4H) 232

MS (ESI) m/z 527.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H),8.58 (d, J = 0.68, 1H), 8.46 (s, 1H), 7.88 (d, J = 7.56 Hz, 1H), 7.47(t, J = 7.72, 1H), 7.41-7.38 (m, 2H), 7.16 (d, J = 8.92, 1H), 7.13 (d, J= 2.52 ,1H), 5.02 (d, J = 46.24 Hz, 2H), 4.28 (s, 4H), 3.73(s, 1H) 233

MS (ESI) m/z 556.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.10 (s,1H),8.49 (s, 1H), 8.40 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.55 (d, J = 7.6Hz, 1H), 7.44-7.39 (m, 2H), 7.28 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 8.84,1H), 5.13 (d, J = 45.76 Hz, 2H), 4.33-4.31 (m, 4H), 3.46 (s, 3H) 234

MS (ESI) m/z 541.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.76 Hz, 1H), 8.36 (d, J = 3.88 Hz, 2H), 8.19 (d, J = 1.08 Hz, 1H),7.5996-7.5708 (m, 1H), 7.45 (d, J = 4.76 Hz, 1H), 7.41 (d, J = 2.6 Hz,1H), 7.35 (d, J = 8.96 Hz, 1H), 6.02 (s, 1H), 4.39 (d, J = 4.76 Hz, 2H),4.2060 (s, 2H), 1.63 (s, 3H) 235

MS (ESI) m/z 594.36 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.3202 (bs,1H), 8.84 (d, J = 4.76 Hz, 1H), 8.34 (s, 1H), 8.31 (d, J = 1.4 Hz, 1H),8.22 (d, J = 1.36 Hz, 1H), 7.6002-7.5717 (m, 1H), 7.46 (d, J = 4.76 Hz,1H), 7.44 (d, J = 2.52 Hz, 1H), 7.36 (d, J = 8.96 Hz, 1H), 6.18 (s, 1H),4.4153 (t, J = 5.32 Hz, 2H), 4.2160 (t, J = 5.4 Hz, 2H), 3.4635 (s, 3H),1.6167 (s, 3H) 236

MS (ESI) m/z 583.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.4 (bs, 1H),8.82 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.77(d, J = 9.2 Hz, 1H), 7.69-7.32 (m, 5H), 4.40-4.38 (m, 2H), 4.24-4.21 (m,2H), 1.74 (s, 3H) 237

MS (ESI) m/z 624.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H),8.85 (d, J = 4.48 Hz, 1H), 8.34 (d, J = 7.72 Hz, 1H), 8.03 (d, J = 7.92,1H), 7.59 (d, J = 8.8 Hz , 1H), 7.51 (d, J = 1.96 Hz, 1H), 7.48 (d, J =4.56 Hz, 1H), 7.35 (d, J = 9 Hz, 1H), 4.41(t, J = 4 Hz, 2H), 4.29 (t, J= 4.28 Hz , 2H), 2.84 (s, 6H). 1.99 (s, 3H) 238

MS (ESI) m/z 610.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (m, 2H),8.30 (d, J = 7.76Hz, 1H), 8.03 (d, J = 7.72 Hz, 1H), 7.58 (d, J = 8.8Hz,1H), 7.52 (d, J = 1.76 Hz, 1H), 7.45 (d, J = 4.44 Hz, 1H), 7.35 (d, J =8.84 Hz, 1H), 4.41 (t, J = 4.6 Hz, 2H), 4.29 (t, J = 4.96 Hz, 2H), 2.54(d, J = 5.92 Hz, 3H). 2.11 (s, 3H) 239

MS (ESI) m/z 576.04 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) 8.82 (d, J =4.8, 1H), 8.75 (s, 1H), 8.55 (s, 1H), 7.61 (dd, J = 2.48 Hz, 8.8 Hz,1H), 7.48 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.36 Hz, 1H), 7.38 (d, J =8.92, 1H), 4.42 (t, J = 4.64 Hz, 2H), 4.29 (t, J = 4.32 Hz, 2H), 1.95(s, 3H) 240

MS (ESI) m/z 560.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.24 (bs,1H), 8.80 (d, J = 4.60 Hz, 1H), 8.68 (d, J = 8.84 Hz, 1H), 8.51 (s, 1H),7.59 (dd, J = 6.64 Hz, 2.8 Hz, 1H), 7.45 (d, J = 4.76 Hz, 1H), 7.43 (d,J = 2.28 Hz, 1H), 7.37 (d, J = 8.84 Hz, 1H), 4.42 (t, J = 4.96 Hz, 2H),4.28 (t, J = 5.04 Hz, 2H), 1.95 (s, 3H) 241

MS (ESI) m/z 553.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 8.83 (d, J =4.76 Hz, 1H), 8.47 (s, 1H), 8.09 (t, J = 9.48 Hz, 1H), 7.60 (dd, J =2.16, 8.8 Hz, 1H), 7.51 (d, J = 4.64 Hz, 1H), 7.41 (d, J = 2.16 Hz, 1H),7.37 (d, J = 8.92 Hz, 1H), 4.42 (bs, 2H). 4.26 (bs, 2H), 1.84 (s, 3H)242

MS (ESI) m/z 569.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.68 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J = 6.84 Hz, 1H), 7.60 (dd, J =2.28 Hz, 8.84 Hz, 1H), 7.48 (d, J = 4.68 Hz, 1H), 7.42 (d, J = 2.32 Hz,1H), 7.35 (d, J = 8.96 Hz, 1H), 4.39 (t, J = 5.64 Hz, 2H), 4.22 (t, J =5.64 Hz, 2H), 1.73 (s, 3H) 243

MS (ESI) m/z 581.08 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (bs,1H), 8.84 (d, J = 4.8 Hz, 1H), 8.40 (s, 1H), 7.65 (d, J = 9.6 Hz, 1H),7.60 (dd, J = 8.8, 2.4 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.42 (d, J =2.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 4.40-4.38 (m, 2H), 4.24-4.22 (m,2H), 1.75 (s, 3H) 244

MS (ESI) m/z 551.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.76 Hz, 1H), 8.39 (s, 1H), 8.06 (d, J = 8.88, 1H), 7.68 (d, J = 8.8,1H), 7.58-7.61 (m, 1H), 7.50 (d, J = 4.56 Hz, 1H), 7.43 (d, J = 2.52 Hz,1H), 7.39 (d,J = 9.0 Hz, 1H), 4.40 (s, 2H), 4.23 (s, 2H), 1.74 (s, 3H)245

MS (ESI) m/z 535.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.33 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.4 (s, 1H), 7.93 (t, J = 9.0 Hz, 1H),7.76 (dd, J = 9.0, 5.0 Hz, 1H), 7.59 (dd, J = 8.8, 2.5 Hz, 1H), 7.51 (d,J = 4.8 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.4(t, J = 4.8 Hz, 2H), 4.23 (t, J = 4.7 Hz, 2H), 1.73 (s, 3H) 247

MS (ESI) m/z 658.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.84 Hz, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 7.60 (dd, J = 2.4, 8.88 Hz,1H), 7.52 (d, J = 4.8 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.36 (d, J =9.2 Hz, 1H), 4.41 (t, J = 4.72 Hz, 2H), 4.23 (t, J = 4.44 Hz, 2H), 2.96(s, 6H), 1.71 (s, 3H) 248

MS (ESI) m/z 636.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.76 Hz, 1H), 8.43 (s, 1H), 8.26 (d, J = 8.72 Hz, 1H), 7.84 (d, J = 8.72Hz, 1H), 7.61 (dd, J = 8.92, 2.6 Hz, 1H), 7.51 (d, J = 4.76 Hz, 1H),7.46 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 5.6 Hz,2H), 4.25 (t, J = 5.52 Hz, 2H), 3.96 (t, J = 7.52 Hz, 4H), 2.19-2.11 (m,2H), 1.76 (s, 3H) 249

MS (ESI) m/z 650.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.40 (s, 1H), 8.28 (d, J = 8.72 Hz, 1H), 7.82 (d, J = 8.76Hz, 1H), 7.60 (dd, J = 8.92, 2.56 Hz, 1H), 7.50 (d, J = 4.76 Hz, 1H),7.45 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.24Hz, 2H), 4.25 (t, J = 1.96 Hz, 2H),3.36 (t, J = 6.48 Hz, 4H), 1.83 (t, J= 6.52, 4H), 1.75 (s, 3H) 250

MS (ESI) m/z 652.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.84 Hz, 1H), 8.43 (s, 1H), 8.31 (d, J = 8.76 Hz, 1H), 7.81 (d, J = 8.8,Hz, 1H), 7.61 (dd, J = 2.72, 8.92 Hz, 1H), 7.52 (d, J = 4.84 Hz, 1H),7.46 (d, J = 2.72 Hz, 1H), 7.36 (d, J = 9.04 Hz, 1H), 4.41 (t, J = 4.56Hz, 2H), 4.24 (t, J = 4.5 Hz, 2H), 3.41 (d, J = 7.04 Hz, 4H), 1.74 ( s,3H), 1.10 (t, J = 7.04 Hz, 6H) 251

MS (ESI) m/z 663.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.76 Hz, 1H), 8.41 (s, 1H), 8.26 (d, J = 8.76 Hz, 1H), 7.82 (d, J = 8.72Hz, 1H),7.60 (dd, J = 8.8, 2.52 Hz, 1H),7.50 (d, J = 4.76 Hz, 1H),7.46(d, J = 2.45 Hz, 1H),7.36 (d, J = 8.96 Hz, 1H), 4.40 (bs, 2H), 4.23 (bs,2H), 3.20 (d, J = 5.2 Hz, 4H), 1.75 (s, 3H), 1.55 (s, 4H), 1.46 (d, J =3.64 Hz, 2H) 252

MS (ESI) m/z 686.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.72 (t, J = 6.1, 1H), 8.4 (s, 1H ) 8.20 (d, J = 8.7, 1H),7.73 (d, J = 8.7 Hz, 1H), 7.60 (dd, J = 2.1, 8.92 Hz, 1H), 7.46 (m, 2H),7.37 (d, J = 9 Hz, 1H), 7.1 (m, 4H), 7.07 (t, J = 7.1 Hz, 1H), 4.39 (d,J = 4.56, 2H), 4.24 (m, 4H), 1.72 (s, 3H) 253

MS (ESI) m/z 714.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J = 8.76 Hz, 1H), 7.80 (d, J = 8.76Hz, 1H), 7.62 (dd, J = 2.68, 8.90 Hz, 1H), 7.51 (d, J = 4.80 Hz, 1H),7.44 (d, J = 2.60 Hz, 1H), 7.38 (d, J = 9.00 Hz, 1H),7.35-7.28 (m, 4H),7.15-7.20 (m, 1H), 4.59 (s, 2H), 4.40 (t, J = 4.64 Hz, 2H), 4.25 (t, J =4.36 Hz, 2H), 3.30 (q, J = 6.92 Hz, 2H), 1.75 (s, 3H), 0.91 (t, J = 7.12Hz, 3H). 254

MS (ESI) m/z 517.17 [M + 1]+; UPLC: 98.39%; 1H NMR (400 MHz, DMSO-d6) δ13.42 (s, 1H), 8.82 (d, J = 4.72 Hz, 1H), 8.37 (s, 1H), 7.95 (d, J =6.52 Hz, 1H), 7.91-7.87 (t, 1H), 7.70 (d, J = 8.16, Hz 1H), 7.60-7.57(dd, J = 2.48 Hz, 1H), 7.47 (d, J = 4.76 Hz, 1H), 7.43 (d, J = 2.52 Hz,1H), 7.35 (d, J = 8.96 Hz, 1H), 4.41-4.22 (m, 4H), 1.77 (s, 3H) 256

MS (ESI) m/z 581.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.22 (bs,1H), 8.83 (s, 1H), 8.80 (d, J = 4.8 Hz, 1H), 8.10 (s, 1H), 7.87 (d, J =8.4 Hz, 1H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H),7.43 (d, J = 4.8 Hz, 1H), 6.48-6.41 (m, 1H), 5.97 (d, J = 16.0 Hz, 1H),4.70 (d, J = 4.4 Hz, 2H), 2.36 (s, 3H) 257

MS (ESI) m/z 579.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.7 Hz, 1H), 8.62 (s, 1H), 8.09 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.69(d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.55 (d, J = 4.8 Hz, 1H), 4.85 (s,2H), 2.09 (s, 3H) 258

MS (ESI) m/z 536.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J =4.7 Hz, 1H), 8.6 (s, 1H), 8.51 (d, J = 1.4 Hz, 1H), 8.32 (d, J = 1.4 Hz,1H), 7.76 (d, J = 9.1 Hz, 1H), 7.68 (m, 2H), 7.53 (d, J = 4.7 Hz, 1H),4.86 (s, 2H), 2.13 (s, 3H). 262

MS (ESI) m/z 601.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.53 (bs,1H), 8.86 (d, J = 4.8 Hz, 1H), 8.46 (s, 1H), 8.06 (d, J = 4.6 Hz, 2H),7.60 (dd, J = 8.8, 2.6 Hz, 1H), 7.52 (d, J = 4.7 Hz, 1H), 7.40 (d, J =2.5 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.41 (m, 2H), 4.19 (m, 2H), 1.46(d, J = 3.3 Hz, 3H) 263

MS (ESI) m/z 608.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.21 (bs,1H), 8.87 (d, J = 4.7 Hz, 1H), 8.56 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H),7.61 (dd, J = 8.8, 2.8 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.39-7.37 (m,2H), 4.45 (m, 2H), 4.33 (m, 2H), 1.92 (s, 3H) 264

MS (ESI) m/z 601.15 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 7.96 (d, J = 1.2 Hz1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.43 (d,J = 2.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 4.40 (t, J = 4.8 Hz, 2H),4.24 (t, J = 4.8 Hz, 2H), 1.73 (s, 3H) 268

MS (ESI) m/z 652.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.80 Hz, 1H), 8.50 (s, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.60 (dd, J =2.60, 2.64 Hz, 1H), 7.52 (d, J = 4.76 Hz, 1H), 7.42-7.38 (m, 2H), 4.47(bs, 2H), 4.39 (bs, 2H), 1.89 (s, 3H) 269

MS (ESI) m/z 634.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.21 (bs,1H), 8.77 (d, J = 4.84 Hz, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 8.36 (s,1H), 7.60-7.58 (m, 1H), 7.48 (d, J = 4.72 Hz, 1H), 7.44-7.17 (m, 3H),4.45 (t, J = 4.47 Hz, 2H), 4.35 (t, J = 4.35 Hz, 2H), 1.99 (s, 3H) 270

MS (ESI) m/z 629.04 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.21 (bs,1H), 8.80 (d, J = 4.80 Hz, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 7.94 (s,1H), 7.62-7.59 (m, 1H), 7.50 (d, J = 4.76 Hz, 1H), 7.42-7.38 (m, 2H),4.47 (t, J = 4.47 Hz, 2H), 4.36 (t, J = 4.36 Hz, 2H), 1.85 (s, 3H) 271

MS (ESI) m/z 605.04 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.30 (bs,1H), 8.84 (d, J = 4.68 Hz, 1H), 8.36 (s, 1H), 8.35 (d, J = 1.38 Hz, 1H),7.98 (s, 1H), 7.58 (dd, J = 2.60, 2.60 Hz, 1H), 7.47 (d, J = 4.72 Hz,1H), 7.43 (d, J = 2.60 Hz, 1H), 7.33 (d, J = 8.96 Hz, 1H), 4.33 (t, J =4.79 Hz, 2H), 4.20 (t, J = 4.94 Hz, 2H), 1.75 (s, 3H) 273

MS (ESI) m/z 558.95 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86-8.85 (d,J = 4.8 Hz, 1H), 8.57 (d, J = 1.2 Hz, 1H), 8.23 (d, J = 1.2 Hz, 1H),8.17 (s, 1H), 7.61-7.58 (dd, J = 2.8, 8.8 Hz, 1H), 7.50-7.49 (d, J = 4.8Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.37-7.35 (d, J = 8.8 Hz, 1H), 4.40(d, J = 4.4 Hz, 2H), 4.18 (t, J 4.4 Hz, 2H), 1.49 (d, J = 3.6 Hz, 3H)274

MS (ESI) m/z 611.97 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J =4.7 Hz, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.59 (d, J = 9.3Hz, 1H), 7.52 (d, J = 4.5 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J = 8.9 Hz,1H), 4.42 (t, J = 5.2 Hz, 2H), 4.19 (t, J = 5.2 Hz, 2H), 3.52 (s, 3H),1.46 (s, 3H) 276

MS (ESI) m/z 559.95 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.81 (bs,1H), 8.85 (d, J = 4.76 Hz, 1H), 8.39 (s, 1H), 7.69 (d, J = 9.60 Hz, 1H),7.60 (dd, J = 8.84, 2.48 Hz, 1H), 7.50 (d, J = 4.76 Hz, 1H), 7.42 (d, J= 2.56 Hz, 1H), 7.36 (d, J = 8.96 Hz, 1H), 4.40 (t, 4.40 Hz, 2H), 4.25(t, J = 4.80, 2H), 1.80 (s, 3H) 277

MS (ESI) m/z 629.53 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.35 (bs,1H), 8.84 (d, J = 4.8 Hz, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.60 (dd, J =8.8, 2.4 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H),7.37 (d, J = 8.8 Hz, 1H), 4.42 (t, J = 4.4 Hz, 2H), 4.25 (t, J = 5.2 Hz,2H), 1.71 (s, 3H) 278

MS (ESI) m/z 613.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.21 (bs,1H), 8.84 (d, J = 3.28 Hz, 1H), 8.26 (s, 1H), 8.07 (d, J = 5.96 Hz, 1H),7.59 (d, J = 7.96 Hz, 1H), 7.47 (bs, 1H), 7.41 (s, 1H), 7.36 (d, J =8.68 Hz, 1H), 4.42 (s, 2H), 4.24 (s, 2H), 3.58 (s, 3H),1.72 (s, 3H) 279

MS (ESI) m/z 613.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.72 Hz, 1H), 8.43 (s, 1H), 7.64 (d, J = 11.36 Hz, 1H), 7.60 (dd, J =8.88, 2.56 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H),7.36 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.24 (t, J = 4.64,2H), 3.58 (s, 3H), 1.78 (s, 3H) 280

MS (ESI) m/z 642.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J =4.84 Hz, 1H), 8.31 (s, 1H), 8.05 (d, J = 6.32 Hz, 1H), 7.59 (dd, J =8.88, 2.56 Hz, 1H), 7.51 (d, J = 4.84 Hz, 1H), 7.45 (d, J = 2.56 Hz,1H), 7.35 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 4.60 Hz, 2H), 4.22 (t, J =4.32 Hz, 2H), 2.94 (s, 6H), 1.62 (s, 3H) 281

MS (ESI) m/z 641.95 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.76 Hz, 1H), 8.40 (s, 1H), 7.64 (d, J = 11.52 Hz, 1H), 7.60 (dd, J =2.60, 8.96 Hz, 1H), 7.48 (d, J = 4.76 Hz, 1H), 7.44 (d, J = 2.64 Hz,1H), 7.36 (d, J = 8.92 Hz, 1H), 4.39 (t, J = 4.4 Hz, 2H), 4.22 (t, J =4.36, 2H), 2.92 (s, 6H), 1.77 (s, 3H) 282

MS (ESI) m/z 700.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.84 Hz, 1H), 8.41 (s, 1H), 8.32 (d, J = 8.76 Hz, 1H), 7.81 (d, J =8.76, Hz, 1H), 7.61 (dd, J = 2.60, 8.92 Hz, 1H), 7.50 (d, J = 4.80 Hz,1H), 7.46 (d, J = 2.68 Hz, 1H), 7.36 (d, J = 9.04 Hz, 1H), 4.41 (bs,2H), 4.24 (bs, 2H), 3.41(m, 4H), 2.14-2.07 (m, 4H), 1.76 (s, 3H) 283

MS (ESI) m/z 700.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.84 Hz, 1H), 8.41 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.8,Hz, 1H), 7.61 (dd, J = 2.72, 8.92 Hz, 1H), 7.505 (d, J = 4.84 Hz, 1H),7.46 (d, J = 2.72 Hz, 1H), 7.36 (m, 6H), 4.48 ( s, 2H), 4.41 ( t, J =4.56 Hz, 2H), 4.24 (t, J = 4.56 Hz, 2H), 2.76 (s, 3H), 1.74 ( s, 3H) 286

MS (ESI) m/z 538.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H),8.80 (d, J = 4.8 Hz, 1H), 8.43 (d, J = 0.8 Hz, 1H), 8.33 (d, J = 0.8 Hz,1H), 7.87 (d, J = 8.8 Hz, 1H ), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.52 (d,J = 2.0 Hz, 1H), 7.45 (d, J = 4.8, 1H), 6.49-6.42 (m,1H), 5.97 (d, J =16 Hz, 1H), 4.71 (d, J = 4.8 Hz, 1H), 2.39 (s 3H) 288

MS (ESI) m/z 642.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.56 Hz, 1H), 8.45 (s, 1H), 8.11 (d, J = 5.2 Hz, 1H), 7.61 (d, J = 7 Hz,1H), 7.52 (d, J = 4.52 Hz, 1H), 7.45 (d, J = 2.12 Hz, 1H), 7.37 (d, J =8.68 Hz, 1H), 4.42 (t, J = 4.6 Hz, 2H), 4.27 (t, J = 6.32 Hz, 2H), 2.89(s, 6H), 1.83 (s, 3H) 290

MS (ESI) m/z 576.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.26 (bs,1H), 8.87 (d, J = 4.6 Hz, 1H), 8.37 (s, 1H), 8.05 (dd, J = 8.7, 2.0 Hz,1H), 7.93 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 3.1 Hz, 1H),7.5 (s, 1H), 4.5 (t, J = 4.8 Hz, 2H), 4.25 (t, J = 4.6 Hz, 2H), 1.69 (s,3H) 293

MS (ESI) m/z 613.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.80 Hz, 1H), 8.75 (bs, 1H), 8.30 (d, J = 8.36 Hz, 1H), 7.60 (dd, J =8.96, 6.52, Hz, 1H), 7.90-7.42 (m, 2H), 7.38 (d, J = 8.88 Hz, 1H), 4.43(t, J = 5.84 Hz, 2H), 4.30 (t, J = 4.24 Hz, 2H), 3.67 (s, 3H), 2.11 (s,3H) 297

MS (ESI) m/z 658.33 [M + 1]+; 1H NMR (400 MHz, DMSO-d6): δ 13.34 (bs,1H), 8.80 (d, J = 4.7 Hz, 1H), 8.65 (d, J = 4.32 Hz, 1H), 8.61 (d, J =8.72 Hz, 1H), 8.48 (s, 1H), 8.37 (d, J = 7.88 Hz, 1H), 8.26 (t, J = 7.76Hz, 1H), 7.96 (d, J = 8.76 Hz, 1H), 7.77-7.74 (m, 1H), 7.58-7.55 (m,1H), 7.46-7.44 (m, 2H), 7.30 (d, J = 8.96 Hz, 1H), 4.34 (d, J = 4.68 Hz,2H), 4.20 (d, J = 4.40 Hz, 2H), 1.75 (s, 3H) 298

MS (ESI) m/z 602.95 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.13 (bs,1H), 8.82 (d, J = 4.76 Hz ,1H), 8.41 (s, 1H), 7.60 (dd, J = 2.64, 8.92Hz, 1H), 7.48- 7.34 (m, 4H), 4.42 (t, J = 4.6 Hz, 2H), 4.26 (t, J = 4.0Hz, 2H), 1.85 (s, 3H) 302

MS (ESI) m/z 609.60 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J =4.6 Hz, 1H), 8.38 (s, 1H), 7.89 (d, J = 9.76 Hz, 1H), 7.60 (dd, J = 2,4,8.84 Hz, 1H), 7.50 (d, J = 4.60 Hz, 1H), 7.47-7.20 (m, 3H), 4.43 (t, J =4.80 Hz, 2H), 4.26 (t, J = 4.88 Hz, 2H), 1.83 (s, 3H) 303

MS (ESI) m/z 613.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H),8.78 (d, J = 4.84 Hz, 1H), 8.32 (s, 1H), 8.05 (s, J = 9.60, 1H), 7.59(dd, J = 8.96, 2.56 Hz, 1H), 7.49-7.35 (m, 4H), 4.41 (m, 2H), 4.27 (m,2H), 3.86 (s, 3H), 1.89 (s, 3H) 304

MS (ESI) m/z 583.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s,1H),7.95 (s, 1H), 7.86-7.85 (m, 3H), 7.53 (d, J = 7.96, 1H), 7.43- 7.38 (m,2H), 7.28 (d, J = 2.6, 1H), 7.20 (d, J = 8.8 Hz, 1H), 4.30 (s, 4H), 2.18(s, 3H) 305

MS (ESI) m/z 638.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.21 (bs,1H), 8.83 (s, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 7.71 (s, 1H), 7.58 (dd, J= 2.44, 8.88 Hz, 1H), 7.47 (bs, 1H), 7.43 (s, 1H), 7.33 (d, J = 8.96 Hz,1H), 4.35 (t, J = 5.32 Hz, 2H), 4.18 (t, J = 5.08 Hz, 2H), 1.71 (s, 3H)306

MS (ESI) m/z 577.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J =4.68 Hz, 1H), 8.39 (s, 1H), 7.61-7.58 (m, 1H), 7.48 (d, J = 4.64 Hz,1H), 7.44-7.35 (m, 3H), 4.40 (t, J = 5.18 Hz, 2H), 4.22 (t, J = 4.48 Hz,2H), 1.73 (s, 3H) 307

MS (ESI) m/z 629.98 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H),8.90 (d, J = 4.80 Hz, 1H), 8.53 (s, 1H), 7.72 (dd, J = 7.60, 10.68 Hz,1H), 7.61 (dd, J = 2.56, 8.88 Hz, 1H), 7.56 (d, J = 4.84 Hz, 1H), 7.44(d, J = 2.64 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 4.56 Hz,2H), 4.23 (t, J = 4.60 Hz, 2H), 3.57 (s, 3H), 1.74 (s, 3H) 308

MS (ESI) m/z 581.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H),8.83 (d, J = 4.76 Hz, 1H), 8.26 (s, 1H), 7.73 (dd, J = 7.24, 10.48 Hz,1H), 7.59 (dd, J = 2.48, 8.88 Hz, 1H), 7.44 (d, J = 4.72 Hz, 1H), 7.40(d, J = 2.52 Hz, 1H), 7.35 (d, J = 9.04 Hz, 1H), 4.38 (t, J = 4.28 Hz,2H), 4.22 (t, J = 4.56 Hz, 2H), 3.88 (s, 3H), 1.75 (s, 3H) 309

MS (ESI) m/z 614.07 [M + 1]+. 1H NMR (400 MHz, DMSO-D2O) δ 8.76 (s, 1H),8.21 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.53 (d, J = 12 Hz, 1H), 7.41(s, 1H), 7.30-7.26 (m, 2H), 4.34 (s, 2H), 4.17 (s, 2H), 3.41 (s, 3H),1.50 (s, 3H) 310

MS (ESI) m/z 600.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 8.11 (s, 1H),7.58 (dd, J = 2.5 Hz, 2.6 Hz, 1H), 7.52 (d, J = 4.7 Hz, 1H), 7.42 (d, J= 2.6 Hz, 1H), 7.36 (d, J = 8 Hz, 1H), 4.41 (t, J = 5.2 Hz, 2H), 4.21(t, J = 5.5 Hz, 2H), 1.54 (s, 3H) 311

MS (ESI) m/z 592.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.72 Hz, 1H), 8.29 (s, 1H), 7.62-7.60 (m, 2H), 7.48 (d, J = 4.76 Hz,1H), 7.43 (d, J = 2.60 Hz, 1H), 7.37 (d, J = 8.96 Hz, 1H), 4.59 (s, 2H),4.41 (t, J = 4.68 Hz, 2H), 4.25 (t, J = 4.68 Hz, 2H), 2.95 (s, 6H), 1.81(s, 3H) 312

MS (ESI) m/z 541.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.23 (bs,1H), 8.8 (d, J = 4.8 Hz, 1H), 8.52 (s, 1H), 8.4 (d, J = 7.8 Hz, 1H),8.06 (d, J = 7.8 Hz, 1H), 7.59 (dd, J = 8.9, 2.6 Hz, 1H), 7.46 (d, J =4.8 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.42(t, J = 4.6 Hz, 2H), 4.28 (t, J = 4.9 Hz, 2H), 1.97 (s, 3H). 313

MS (ESI) m/z 600.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.23 (bs,1H), 8.77 (d, J = 4.76 Hz, 1H), 8.55 (s, 1H), 8.02 (d, J = 8.28 Hz, 1H),7.92 (d, J = 7.24 Hz, 1H), 7.58 (dd, J = 2.56, 8.88 Hz, 1H), 7.46-7.44(m, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.41 (t, J = 5.32 Hz, 2H), 4.26 (t,J = 4.52 Hz, 2H), 1.90 (s, 3H). 316

MS (ESI) m/z 560.39 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.92 (d, J = 8.36 Hz, 2H), 7.69(d, J = 8.52 Hz, 1H), 7.60-7.58 (m, 1H), 7.48 (d, J = 4.84 Hz, 1H), 7.44(d, J = 2.68 Hz, 1H), 7.35 (d, J = 8.96 Hz, 1H), 4.39 (t, J = 4.48 Hz,2H), 4.23 (t, J = 4.48 Hz, 2H), 1.72 (s, 3H) 317

MS (ESI) m/z 559.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.34 (bs,1H), 8.81 (d, J = 4.4 Hz, 1H), 8.45 (s, 1H), 8.28 (s, 2H), 8.20 (s, 1H),7.87 (s, 1H), 7.59-7.57 (m, 1H), 7.50-7.40 (m, 2H), 7.35 (d, J = 8.8 Hz,1H), 4.49-4.30 (m, 2H), 4.29-4.15 (m, 2H), 1.77 (s, 3H) 318

MS (ESI) m/z 662.04 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H),8.78 (d, J = 4.76 Hz, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 7.60-7.58 (m,1H), 7.47-7.44 (m, 2H), 7.38 (d, J = 8.92 Hz, 1H), 4.44 (s, 4H), 3.27(s, 3H), 2.33 (s, 3H) 334

MS (ESI) m/z 586.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 9.20 (b,2H), 8.30 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.55 (s, 1H), 7.44(s, 1H), 7.39-7.35 (m, 2H), 4.53-4.48 (m, 2H), 4.41 (bt, 2H), 4.26 (bt,2H), 3.57 (2H; observed by HSQC, signal is obscured by water peak in1H-NMR), 3.22 (bt, 2H), 2.73 (s, 3H), 1.97 (s, 3H) 335

MS (ESI) m/z 600.7 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 10.30 (b,1H), 8.27 (bs, 1H), 7.63-7.58 (m, 1H), 7.52 (bs, 1H), 7.45-7.34 (m, 4H),4.88- 4.12 (m, 6H), 3.04 (s, 3H), 2.72 (s, 3H), 1.92 (s, 3H) [remainingsignals obscured by water or solvent peak] 336

MS (ESI) m/z 600.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 10.46-10.14 (b, 1H), 8.26 (s, 1H), 7.60 (dd, J = 9.0, 2.8 Hz, 1H), 7.54 (s,1H), 7.43 (s, 1H), 7.40-7.35 (m, 2H), 4.93-3.38 (m, 6H; partiallyobscured by water peak), 4.43-4.35 (b, 2H), 3.38-3.27 (b, 2H), 3.10 (s,3H), 2.73 (s, 3H), 1.93 (s, 3H) 337

MS (ESI) m/z 575.0 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 9.07 (d,J = 1.9 Hz, 1H), 8.30 (s, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.59 (dd, J =8.9, 2.6 Hz, 1H), 7.43-7.41 (m, 2H), 7.35 (d, J = 8.9 Hz, 1H), 4.39 (t,J = 5.0 Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H), 2.70 (s, 3H), 1.80 (s, 3H)345a

MS (ESI) m/z 676.6 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.31 (s,1H), 8.19 (s, 1H), 8.07-8.04 (m, 1H), 7.93-7.88 (m, 1H), 7.80-7.74 (m,2H), 7.59 (dd, J = 8.9, 2.6 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J = 2.6 Hz,1H), 7.35 (d, J = 8.9 Hz, 1H), 4.41 (t, J = 4.8 Hz, 2H), 4.27 (t, J =4.8 Hz, 2H), 2.74 (s, 3H), 1.82 (s, 3H) 345b

MS (ESI) m/z 694.1 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.29 (s,1H), 8.07 (s, 1H), 8.01-7.95 (b, 1H), 7.88 (dd, J = 7.7, 1.7 Hz, 1H),7.65-7.55 (m, 3H), 7.46-7.39 (m, 3H), 7.33 (d, J = 9.0 Hz, 1H),7.21-7.15 (b, 1H), 4.40 (t, J = 4.7 Hz, 2H), 4.27-4.20 (b, 2H), 2.74 (s,3H), 1.74 (s, 3H) 346

MS (ESI) m/z 681.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 8.33 (s,1H), 8.23 (s, 1H), 7.62-7.56 (m, 2H), 7.51 (dt, J = 7.6, 1.4 Hz, 1H),7.46-7.42 (m, 2H), 7.40-7.35 (m, 1H), 7.35 (d, J = 9.0 Hz, 1H),7.32-7.28 (m, 1H), 4.43-4.34 (m, 2H), 4.29-4.18 (m, 4H), 2.73 (s, 3H),1.81 (s, 3H) 351a

MS (ESI) m/z 590.0 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) d/ppm = 11.72 (s,1H), 8.44 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (d, J = 2.7 Hz,1H), 7.40 (s, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.17-7.16 (m, 1H),7.07-7.05 (m, 1H), 4.40 (t, J = 4.9 Hz, 1H), 4.25 (t, J = 4.9 Hz, 2H),2.68 (s, 3H), 1.88 (s, 3H) 351b

MS (ESI) m/z 574.0 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) d/ppm = 8.35 (s,1H), 8.18-8.14 (m, 1H), 7.76-7.71 (m, 1H), 7.58 (dd, J = 8.9, 2.8 Hz,1H), 7.42 (d, J = 2.8 Hz, 1H), 7.40 (s, 1H), 7.34 (d, J = 8.9 Hz, 1H),4.38 (t, J = 4.9 Hz, 2H), 4.24 (t, J = 4.9 Hz, 2H), 2.69 (s, 3H), 1.84(s, 3H) 353

MS (ESI) m/z 584.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.9 Hz, 1H), 8.61 (s, 1H), 8.18-8.17 (m, 1H), 8.16-8.15 (m, 1H), 7.67(s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.47 (s, 1H), 7.46 (d, J = 2.3Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 4.30 (t, J = 6.2 Hz, 2H), 3.70 (s,3H), 2.71 (t, J = 6.2 Hz, 2H) 355

MS (ESI) m/z 615.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.87-8.84 (m,2H), 7.61-7.57 (m, 2H), 7.53-7.51 (m, 2H), 7.38 (d, J = 9.0 Hz, 1H),7.35 (s, 1H), 4.23 (t, J = 5.5 Hz, 2H), 3.74 (t, J = 5.4 Hz, 2H), 2.75(s, 3H), 1.07 (s, 6H) 357

MS (ESI) m/z 598.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.51 (s, 1H), 8.27-8.26 (m, 1H), 8.16 (dd, J = 1.5, 0.6 Hz,1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.41 (d,J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.23 (t, J = 6.1 Hz, 2H),3.62 (s, 3H), 2.89 (t, J = 6.1 Hz, 2H), 1.85 (s, 3H) 358

MS (ESI) m/z 585.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =4.8 Hz, 1H), 8.63 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 7.8Hz, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.48-7.43 (m, 2H), 7.37 (d, J =9.0 Hz, 1H), 4.44 (t, J = 5.1 Hz, 2H), 4.29 (t, J = 5.1 Hz, 2H), 1.98(s, 3H). 359

MS (ESI) m/z 583.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J =4.3 Hz, 1H), 8.55 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.2Hz, 1H), 7.60 (dd, J = 9.0, 2.6 Hz, 1H), 7.52-7.29 (m, 4H), 4.42 (t, J =4.2 Hz, 2H), 4.26 (t, J = 4.4 Hz, 2H), 1.92 (s, 3H) 360

MS (ESI) m/z 567.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.55 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 7.8Hz, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.51 (t, J = 54.6 Hz, 1H). 7.44(d, J = 2.7 Hz, 1H), 7.43 (d, J = 4.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H),4.42 (t, J = 5.0 Hz, 2H), 4.25 (t, J = 5.0 Hz, 2H), 1.84 (s, 3H) 361

MS (ESI) m/z 632.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 7.57 (dd, J = 8.9, 2.7 Hz, 1H),7.48 (d, J = 4.8 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz,1H), 4.24 (t, J = 5.9 Hz, 2H), 3.60 (s, 3H), 2.89 (t, J = 5.9 Hz, 2H),1.80 (s, 3H) 362

MS (ESI) m/z 630.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 8.18 (d, J = 1.2 Hz, 1H), 7.57(dd, J = 8.9, 2.7 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.46 (d, J = 2.7Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 4.76 (t, J = 4.4 Hz, 1H), 4.73-4.66(m, 1H), 4.64 (s, 2H), 4.21 (t, J = 6.3 Hz, 2H), 2.93 (t, J = 6.3 Hz,2H), 2.02 (s, 3H) 366

MS (ESI) m/z 661.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H),8.34 (s, 1H), 7.60 (dd, J = 8.9, 2.6 Hz, 1H), 7.48 (d, J = 10.1 Hz, 1H),7.46-7.39 (m, 2H), 7.36 (d, J = 8.9 Hz, 1H), 4.39 (t, J = 4.9 Hz, 2H),4.24 (t, J = 5.0 Hz, 2H), 3.83 (s, 2H), 3.06-2.92 (m, 4H), 2.77 (d, J =4.0 Hz, 3H), 2.71 (s, 3H), 1.88 (s, 3H) 367

MS (ESI) m/z 648.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H),7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.55 (d, J = 10.1 Hz, 1H), 7.43 (s, 1H),7.42 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.1 Hz,2H), 4.25 (t, J = 5.1 Hz, 3H), 3.70 (bs, 4H), 2.99 (bs, 4H), 2.72 (s,3H), 1.88 (s, 3H) 368

MS (ESI) m/z 563.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H),7.60 (dd, J = 9.0, 2.7 Hz, 1H), 7.44- 7.39 (m, 3H), 7.36 (d, J = 9.0 Hz,1H), 4.39 (t, J = 5.1 Hz, 2H), 4.24 (t, J = 5.1 Hz, 2H), 2.72 (s, 3H),2.50 (s, 3H), 1.91 (s, 3H) 369

MS (ESI) m/z 618.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H),8.50 (s, 1H), 7.96 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.44 (s,1H), 7.41 (d, J = 2.6 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 4.64 (d, J =4.6 Hz, 2H), 4.43 (t, J = 5.0 Hz, 2H), 4.27 (t, J = 4.9 Hz, 2H), 2.79(d, J = 4.0 Hz, 6H), 2.70 (s, 3H), 1.99 (s, 3H) 370

MS (ESI) m/z 646.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H),8.53 (s, 1H), 7.96 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.44 (s,1H), 7.42 (d, J = 2.6 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 4.89 (hept, J =6.0 Hz, 1H), 4.62 (d, J = 4.9 Hz, 2H), 4.42 (t, J = 5.0 Hz, 2H), 4.26(t, J = 5.0 Hz, 2H), 2.78 (d, J = 4.3 Hz, 6H), 2.69 (s, 3H), 1.93 (s,3H), 1.42 (d, J = 6.0 Hz, 6H) 371

MS (ESI) m/z 589.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H),7.76 (d, J = 9.4 Hz, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 8.9,2.7 Hz, 1H), 7.44-7.39 (m, 2H), 7.36 (d, J = 9.0 Hz, 1H), 4.92 (hept, J= 6.0 Hz, 1H), 4.38 (t, J = 5.1 Hz, 2H), 4.21 (t, J = 5.1 Hz, 2H), 2.71(s, 3H), 1.79 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H) 390

MS (ESI) m/z 666.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H),8.17 (s, 1H), 8.03 (s, 1H), 7.58 (dd, J = 8.9, 2.7 Hz, 1H), 7.51 (s,1H), 7.43-7.39 (m, 2H), 7.33 (d, J = 9.0 Hz, 1H), 4.68 (s, 2H), 4.37 (t,J = 4.4 Hz, 2H), 4.21 (t, J = 4.5 Hz, 2H), 2.71 (s, 3H), 1.79 (s, 3H)391

MS (ESI) m/z 631.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H),8.05 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J =2.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.24(t, J = 5.0 Hz, 2H), 3.01-2.93 (m, 2H), 2.71 (s, 3H), 1.81 (s, 3H),1.79-1.70 (m, 2H), 1.42 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H)392

MS (ESI) m/z 674.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J =2.8 Hz, 1H), 8.40 (s, 1H), 7.98 (dd, J = 9.1, 2.9 Hz, 1H), 7.90 (s, 1H),7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 2.6 Hz, 1H),7.37 (d, J = 9.0 Hz, 1H), 4.42 (t, J = 5.1 Hz, 2H), 4.35-4.17 (m, 2H),2.74 (s, 3H), 2.25 (s, 3H), 1.89 (s, 3H) 393

MS (ESI) m/z 656.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H),8.42 (s, 1H), 7.86 (s, 1H), 7.64-7.56 (m, 2H), 7.52 (d, J = 5.0 Hz, 1H),7.43 (s, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.41(t, J = 5.1 Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H), 2.73 (s, 3H), 2.64 (s,3H), 1.90 (s, 3H) 394

MS (ESI) m/z 660.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =2.8 Hz, 1H), 8.63 (t, J = 1.7 Hz, 1H), 8.43 (s, 1H), 8.12 (ddd, J = 9.6,2.8, 1.7 Hz, 1H), 7.87 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s,1H), 7.41 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.41 (t, J =5.1 Hz, 2H), 4.31-4.23 (m, 3H), 2.73 (s, 3H), 1.94 (s, 3H) 395

MS (ESI) m/z 656.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.66 (dd, J =5.0, 1.7 Hz, 1H), 8.41 (s, 1H), 7.92-7.87 (m, 2H), 7.60 (dd, J = 8.9,2.7 Hz, 1H), 7.52 (dd, J = 7.7, 4.9 Hz, 1H), 7.45 (s, 1H), 7.44 (d, J =2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 5.0 Hz, 2H),4.32-4.18 (m, 2H), 2.73 (s, 3H), 2.29 (s, 3H), 1.86 (s, 3H) 396

MS (ESI) m/z 670.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H),7.87 (s, 1H), 7.69 (s, 2H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.44 (s,1H), 7.42 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.41 (t, J =5.1 Hz, 2H), 4.27 (t, J = 5.0 Hz, 2H), 2.73 (s, 3H), 2.70 (s, 6H), 1.91(s, 3H) 397

MS (ESI) m/z 685.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H),8.24 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.83 (s, 1H), 7.60(dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.37(d, J = 9.0 Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 4.40 (t, J = 5.1 Hz, 2H),4.26 (t, J = 5.0 Hz, 2H), 3.21 (s, 6H), 2.73 (s, 3H), 1.92 (s, 3H) 399

MS (ESI) 699.3 m/z [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.02-8.95 (m,2H), 8.67 (tt, J = 7.7, 1.3 Hz, 1H), 8.36 (s, 1H), 8.22-8.15 (m, 2H),7.85 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.45- 7.40 (m, 2H), 7.35(d, J = 9.0 Hz, 1H), 6.22 (s, 2H), 4.37 (t, J = 4.9 Hz, 2H), 4.22 (t, J= 5.0 Hz, 2H), 2.71 (s, 3H), 1.87 (s, 3H) 403

MS (ESI) m/z 547.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.33 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 8.9,2.7 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.37(dd, J = 8.9, 2.9 Hz, 2H), 4.42 (t, J = 5.1 Hz, 2H), 4.24 (t, J = 5.1Hz, 2H), 3.97 (s, 3H), 1.83 (s, 3H) 404

MS (ESI) m/z 547.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.41 (s, 1H), 7.76 (d, J = 9.3 Hz, 1H), 7.70 (d, J = 9.3Hz, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.42(d, J = 2.6 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.39 (t, J = 5.0 Hz, 2H),4.21 (t, J = 5.0 Hz, 2H), 4.04 (s, 3H), 1.74 (s, 3H) 405

MS (ESI) m/z 547.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J =4.9 Hz, 1H), 8.38 (s, 1H), 7.60 (dd, J = 8.9, 2.6 Hz, 1H), 7.57 (d, J =2.5 Hz, 1H), 7.54 (d, J = 4.9 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.36(d, J = 9.0 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H), 4.39 (t, J = 5.0 Hz, 2H),4.20 (t, J = 5.0 Hz, 2H), 3.99 (s, 3H), 1.72 (s, 3H). 406

MS (ESI) m/z 601.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.9 Hz, 1H), 8.44 (s, 1H), 8.05-8.00 (m, 1H), 7.84 (d, J = 9.1 Hz, 1H),7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.51 (d, J = 4.9 Hz, 1H), 7.45 (d, J =2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 4.9 Hz, 2H), 4.25(t, J = 4.9 Hz, 2H), 1.78 (s, 3H) 407

MS (ESI) m/z 569.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.48 (s, 1H), 8.17 (d, J = 9.5 Hz, 1H), 7.60 (dd, J = 8.9,2.6 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.37(d, J = 9.0 Hz, 1H), 4.42 (t, J = 5.0 Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H),1.84 (s, 3H) 408

MS (ESI) m/z 617.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.54 (s, 1H), 8.19 (s, 1H), 7.80 (s, 1H), 7.60 (dd, J =8.9, 2.7 Hz, 1H), 7.47 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H),7.36 (d, J = 8.9 Hz, 1H), 4.57 (bs, 2H), 4.40 (t, J = 5.0 Hz, 2H), 4.26(t, J = 5.0 Hz, 2H), 2.87 (s, 6H), 1.80 (s, 3H) 409

MS (ESI) m/z 612.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H),8.26 (s, 1H), 8.16 (bd, J = 1.1 Hz, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H),7.44 (s, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.23(t, J = 6.1 Hz, 2H), 3.63 (s, 3H), 2.90 (t, J = 6.1 Hz, 2H), 2.70 (s,3H), 1.94 (s, 3H). 412

MS (ESI) m/z 573.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.9 Hz, 2H), 8.45 (s, 1H), 8.26 (bs, 1H), 8.16 (bs, 1H), 7.59 (dd, J =8.8, 2.6 Hz, 1H), 7.46 (bs, 1H), 7.44 (bs, 1H), 7.35 (d, J = 9.0 Hz,1H), 4.40 (t, J = 5.3 Hz, 2H), 4.24 (t, J = 5.3 Hz, 2H), 2.87 (d, J =4.5 Hz, 3H), 1.78 (s, 3H) 413

MS (ESI) m/z 588.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J =4.8 Hz, 1H), 8.37 (s, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.60 (dd, J = 8.9, 2.6 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.45(d, J = 2.7 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.3 Hz, 2H),4.23 (t, J = 5.3 Hz, 2H), 3.05 (s, 3H), 3.01 (s, 3H), 1.69 (s, 3H) 426

MS (ESI) m/z 651.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.70 (m, 1H),8.41 (s, 1H), 8.03 (s, 1H), 7.99 (tdd, J = 7.7, 3.1, 1.8 Hz, 1H), 7.85(s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.51(m, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.34 (d, J= 9.0 Hz, 1H), 4.39 (t, J = 5.0 Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H), 2.69(s, 3H), 1.85 (s, 3H) 427

MS (ESI) m/z 672.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H),7.98 (s, 1H), 7.70 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.41 (d, J =2.6 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 4.39 (t, J = 5.1Hz, 2H), 4.24 (t, J = 5.0 Hz, 3H), 3.59-3.50 (m, 2H), 3.26-3.10 (m, 6H),2.93 (s, 3H), 2.69 (s, 3H), 1.84 (s, 3H) 436

MS (ESI) m/z 666.5 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.71 (bs, 2H),8.33 (s, 1H), 8.32 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.54 (br,1H), 7.45 (s, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H),4.40 (t, J = 4.5 Hz, 2H), 4.27 (d, J = 4.5 Hz, 2H), 2.74 (s, 3H), 2.06(bs, 3H), 1.84 (s, 3H) 438

MS (ESI) m/z 690.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J =2.9 Hz, 1H), 8.41 (s, 1H), 7.98 (s, 1H), 7.88 (dd, J = 9.0, 2.9 Hz, 1H),7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 2.7 Hz, 1H),7.37 (d, J = 9.0 Hz, 1H), 6.89 (t, J = 53.7 Hz, 1H), 4.48-4.38 (m, 2H),4.37-4.19 (m, 2H), 2.73 (s, 3H), 2.18 (s, 3H), 1.89 (s, 3H) 439a

MS (ESI) m/z 624.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H),7.77 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H),7.41 (s, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.16 (t, J = 54.4 Hz, 1H), 4.39(t, J = 5.0 Hz, 2H), 4.22 (t, J = 5.0 Hz, 2H), 2.97 (s, 6H), 2.69 (s,3H), 1.82 (s, 3H) 439b

MS (ESI) m/z 597.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H),7.72 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H),7.41 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.15 (t, J = 54.2 Hz, 1H), 4.38(t, J = 5.0 Hz, 3H), 4.21 (t, J = 5.0 Hz, 3H), 2.69 (s, 3H), 1.78 (s,3H) 440

MS (ESI) m/z 671.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.73 (dd, J =5.2, 1.7 Hz, 1H), 8.41 (s, 1H), 7.98 (bd, J = 5.9 Hz, 2H), 7.64-7.56 (m,2H), 7.45 (s, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H),6.84 (t, J = 53.7 Hz, 1H), 4.48-4.37 (m, 2H), 4.37-4.16 (m, 2H), 2.72(s, 3H), 2.27 (s, 3H), 1.87 (s, 3H). 449

MS (ESI) m/z 656.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H),8.05 (s, 1H), 7.70- 7.17 (m, 5H), 4.49 (s, 2H), 4.42 (t, J = 5.0 Hz,2H), 4.27 (t, J = 5.0 Hz, 2H), 2.86 (s, 6H), 2.72 (s, 3H), 1.87 (s, 3H)451

MS (ESI) m/z 731.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H),9.79 (s, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.62 (dd, J = 8.9, 2.7 Hz,1H), 7.51 (s, 1H), 7.44-7.36 (m, 2H), 7.25 (s, 1H), 4.51 (s, 2H), 4.43(d, J = 5.3 Hz, 2H), 4.27 (d, J = 5.1 Hz, 2H), 3.56 (s, 3H), 2.85 (s,6H), 2.74 (s, 3H), 1.83 (s, 3H) 456

MS (ESI) m/z 601.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =4.7 Hz, 1H), 8.35 (s, 1H), 8.07-8.03 (m, 1H), 7.60-7.56 (m, 1H), 7.55(d, J = 2.7 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H),7.32 (d, J = 9.0 Hz, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.20 (t, J = 5.0 Hz,2H), 1.70 (s, 3H) 457

MS (ESI) m/z 604.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J =4.8 Hz, 1H), 8.36 (s, 1H), 7.78 (d, J = 9.3 Hz, 1H), 7.70 (d, J = 9.2Hz, 1H), 7.57 (dd, J = 9.0, 2.7 Hz, 1H), 7.44 (d, J = 4.8 Hz, 1H), 7.39(d, J = 2.7 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 4.68-4.55 (m, 2H), 4.36(t, J = 5.1 Hz, 2H), 4.20 (d, J = 5.2 Hz, 2H), 3.62 (s, 2H), 2.96-2.87(m, 7H), 1.77 (s, 3H) 458

MS (ESI) m/z 640.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J =4.8 Hz, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.63-7.17 (m, 5H), 4.54- 4.42(m, 2H), 4.39 (t, J = 5.0 Hz, 2H), 4.24 (t, J = 5.0 Hz, 2H), 2.83 (s,6H), 1.79 (s, 3H) 460

LCMS: 708.6 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.05 (s,1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.44-7.38 (m, 2H), 7.35 (d, J = 8.9Hz, 1H), 4.38 (t, J = 5.0 Hz, 2H), 4.24 (t, J = 5.0 Hz, 2H), 2.75 (d, J= 1.6 Hz, 3H), 2.69 (s, 3H), 1.78 (s, 3H) 461

LCMS: 652.5 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 2H), 8.34 (s,1H), 8.28 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 11.7, 8.4, 3.8Hz, 2H), 7.46-7.41 (m, 2H), 7.36 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 5.0Hz, 2H), 4.27 (t, J = 5.0 Hz, 2H), 2.72 (s, 3H), 1.84 (s, 3H) 462

LCMS: 652.5.6 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.69 (dd, J = 4.9,1.6 Hz, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 8.03 (td, J = 7.7, 1.8 Hz, 1H),7.84 (d, J = 8.0 Hz, 1H), 7.61-7.52 (m, 2H), 7.45-7.41 (m, 2H), 7.35 (d,J = 9.0 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.27 (t, J = 5.1 Hz, 2H),2.70 (s, 3H), 1.82 (s, 3H) 463

LCMS: 666.6 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 5.5 Hz,1H), 8.31 (d, J = 6.8 Hz, 2H), 7.67 (s, 1H), 7.59 (dd, J = 8.9, 2.8 Hz,2H), 7.45- 7.41 (m, 2H), 7.35 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.0 Hz,2H), 4.27 (t, J = 5.0 Hz, 2H), 2.73 (s, 3H), 2.67 (s, 3H), 1.84 (s, 3H)464

LCMS: 652.5 [M + H]+; 1H NMR (400 MHz, DMSO-d6); 1H NMR (400 MHz,DMSO-d6) δ 8.84 (s, 2H), 8.35 (s, 1H), 8.30 (s, 1H), 7.69 (d, J = 5.5Hz, 2H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.46- 7.41 (m, 2H), 7.36 (d, J= 9.0 Hz, 1H), 4.40 (t, J = 4.9 Hz, 2H), 4.27 (t, J = 4.9 Hz, 2H), 2.73(s, 3H), 1.84 (s, 3H) 467

LCMS: 651.8 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.24 (s,1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.53 (s, 5H), 7.43 (d, J = 3.1 Hz,2H), 7.36 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.26 (t, J =4.9 Hz, 2H), 2.71 (s, 3H), 1.83 (s, 3H) 488

LCMS: 635.9 [M + H]+; 1H NMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 7.93(d, J = 9.8 Hz, 1H), 7.58-7.51 (m, 2H), 7.42 (d, J = 2.6 Hz, 1H), 7.29(d, J = 8.9 Hz, 1H), 7.23 (s, 1H), 4.48 (t, J = 4.8 Hz, 2H), 4.40 (t, J= 4.7 Hz, 2H), 2.91 (s, 3H), 2.11 (s, 3H) 490

MS (ESI) m/z 593.7 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.14 (dd, J =7.3, 1.5 Hz, 1H), 8.04 (d, J = 9.7 Hz, 1H), 7.61 (dd, J = 8.9, 2.7 Hz,1H), 7.58 (s, 1H), 7.51-7.46 (m, 1H), 7.39 (s, 1H), 7.36 (d, J = 4.1 Hz,1H), 7.33 (d, J = 2.6 Hz, 1H), 7.31-7.25 (m, 1H), 7.22 (s, 0H), 4.50-4.08 (m, 4H), 2.78 (s, 3H), 1.84 (s, 3H) 493

MS (ESI) m/z 627.12 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 13.29 (bs,1H), 8.84 (d, J = 4.68, 1H), 8.38 (s, 1H), 7.89 (s, 1H), 7.60 (dd, J =2.56, 9.3 Hz, 1H), 7.47 (d, J = 4.6 Hz, 1H), 7.42 (d, J = 1.96 Hz,1H),7.34 (d, J = 8.84 Hz, 1H) 4.39 (t, J = 4.7 Hz, 2H), 4.23 (t, J =4.76, 2H), 3.60 (s, 3H), 1.75 (s, 3H) 497

MS (ESI) m/z 619.47 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =4.8 Hz, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 7.60 (dd, J = 8.88, 2.68 Hz1H), 7.47-7.21 (m, 4H), 4.42 (t, J = 5.12, 2H), 4.28 (t, J = 4.88 Hz,2H), 1.89 (s, 3H) 498

MS (ESI) m/z 619.47 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.44 (s, 1H), 7.66-7.59 (m, 5H), 4.42 (t, J = 9.04 Hz, 2H),4.27 (t, J = 8.6 Hz, 2H), 1.84 (s, 3H) 499

MS (ESI) m/z 593.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1 H),8.85 (d, J = 4.8 Hz, 1H), 7.83 (d, J = 3.6 Hz, 2H), 7.64 (s, 1H), 7.60(dd, J = 8.8 Hz, 2.46 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.98 (s, 1H),3.63 (t, J = 6.8 Hz, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H) 500

MS (ESI) m/z 599.53 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.92 Hz, 1H), 8.08 (d, J = 9.72 Hz, 1H), 7.61 (dd, J = 8.80, 2.64 Hz,1H), 7.53 (d, J = 4.96 Hz, 1H), 7.49- 7.22 (m, 3H), 4.44 (t, J = 5.40Hz, 2H), 4.29 (t, J = 4.84 Hz, 2H). 2.60-2.40 (merged, 3H), 1.96 (s, 3H)504

MS (ESI) m/z 603.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.80 Hz, 1H), 8.46 (s, 1H), 8.05 (d, J = 9.60 Hz, 1H), 7.65 (d, J = 8.32Hz, 1H), 7.56 (d, J = 11.32 Hz, 1H), 7.51-7.36 (m, 2H), 4.45 (t, J =4.72 Hz, 2H), 4.28 (t, J = 6.96 Hz, 2H), 1.86 (s, 3H) 506

MS (ESI) m/z 571.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.48 Hz, 1H), 8.41 (s, 1H), 7.74-7.70 (m, 1H), 7.62 (d, J = 8.36 Hz,1H), 7.55 (d, J = 11.28 Hz, 1H), 7.48 (d, J = 4.48 Hz, 1H), 4.42 (t, J =4.20 Hz, 2H). 4.23 (t, J = 4.20 Hz, 2H), 1.75 (s, 3H) 507

MS (ESI) m/z 588.17 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.30 (bs,1H), 9.71 (bs, 1H), 8.81 (d, J = 4.76 Hz ,1H), 8.35 (s, 1H), 7.91(d, J =8.52 Hz, 1H),7.68 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 2.40, 8.84 Hz, 1H),7.46 (d, J = 4.72 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.37 (d, J = 8.88Hz, 1H), 4.40 (s, 2H), 4.25 (s, 2H), 3.4-3.41 (m, 2H), 3.33 (t, J = 3.84Hz ,2H), 2.92 (s, 6H) ,1.83 (s, 3H) 508

MS (ESI) m/z 592.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.23 (bs,1H), 8.81 (d, J = 4.60 Hz, 1H), 8.34 (s, 1H), 8.09 (d, J = 10.08 Hz,1H), 7.61-7.58 (m, 1H), 7.48 (d, J = 4.64 Hz, 1H), 7.42 (d, J = 2.0 Hz,1H), 7.38 (d, J = 8.88 Hz, 1H), 4.58 (bs, 2H), 4.43 (t, J = 6.08 Hz,2H), 4.28 (t, J = 5.24 Hz, 2H), 2.90 (s, 6H), 1.87 (s, 3H) 509

MS (ESI) m/z 608.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.24 (bs,1H), 8.82 (d, J = 4.72 Hz, 1H), 8.35 (bs, 1H), 7.79 (bs, 1H), 7.60 (dd,J = 2.44, 8.84 Hz, 1H), 7.47 (d, J = 4.72 Hz, 1H), 7.42 (d, J = 2.56 Hz,1H), 7.35 (d, J = 8.92 Hz, 1H), 4.39 (t, J = 5.4 Hz, 2H), 4.23 (t, J =6.12 Hz, 2H), 3.75 (bs, 2H), 2.26 (bs, 6H), 1.77 (s, 3H) 510

MS (ESI) m/z 599.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.76 Hz, 1H), 8.26 (s, 2H), 7.61 (dd, J = 8.84, 2.52 Hz, 1H), 7.48 (d, J= 4.76, Hz, 1H), 7.43 (d, J = 2.56 Hz, 1H), 7.37 (d, J = 8.96 Hz, 1H),4.55 (bs, 2H), 4.42 (bs, 2H), 4.27 (b s, 2H), 2.90 (bs, 6H), 1.82 (s,3H) 511

MS (ESI) m/z 598.21 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.72 Hz,1H), 8.32 (s, 1H), 8.24 (s, 1H), 7.59 (dd, J = 2.44, 2.48 Hz,1H), 7.45 (d, J = 4.72 Hz, 1H), 7.40-7.36 (m, 2H), 6.06 (s, 1H), 4.59(bs, 2H), 4.43 (t, J = 4.36 Hz, 2H), 4.24 (t, J = 4.68 Hz, 2H), 2.93(bs, 6H), 1.69 (s, 3H) 512

MS (ESI) m/z 574.38. [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 9.96 (bs,1H), 8.82 (d, J = 4.72 Hz ,1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.83 (s,1H), 7.61 (dd, J = 2.32, 8.84 Hz, 1H), 7.49 (d, J = 4.68 Hz), 7.44 (d, J= 2.32, 1H), 7.38 (d = 8.96 Hz), 4.46 (s, 2H), 4.41 (t, J = 5.12 Hz,2H), 4.25 (t, J = 5.08 Hz, 2H), 2.83 (s, 6H), 1.79 (s, 3H) 513

MS (ESI) m/z 588.22 [M + 1]+. 1H-NMR (400 MHz, DMSO-d6) δ 9.49 (bs, 1H),8.86 (dd, J = 4.76, 8.85 Hz, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.60 (s,1H),7.59 (d, J = 7.59 Hz, 1H), 7.45 (d, J = 2.28, Hz, 1H), 7.42 (d, J =2.52 Hz, 1H), 7.35 (d, J = 8.92 Hz, 1H), 4.40 (t, J = 5.76 Hz, 2H), 4.22(t, J = 6.32 Hz, 2H), 3.51 (t, J = 4.56. Hz, 2H), 3.18 (t, J = 8.0 Hz,2H), 2.88 (s, 6H), 1.75 (s, 3H) 514

MS (ESI) m/z 623.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (bs, 1H),8.20 (s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 9.0 Hz, 1H),7.45-7.36 (m, 2H), 7.32 (d, J = 8.92 Hz, 1H), 4.37 (t, J = 4.44 Hz, 2H)4.23 (t, J = 4.08 Hz, 2H), 3.21 (t, J = 14.48 Hz, 2H), 2.25 (s, 6H),1.75 (s, 3H). 515

MS (ESI) m/z 624.14 [M + 1]+. 1H-NMR (400 MHz, DMSO-d6) δ 9.69 (bs, 1H),8.80 (d, J = 4.4 Hz, 1H), 8.46 (s, 1H), 8.05 (bs, 1H), 7.68-7.35 (m,5H), 4.64 (bs, 2H), 4.41 (s, 2H), 4.26 (s, 2H), 2.83 (bs, 6H), 1.79 (s,3H) 516

MS (ESI) m/z 607.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.76 Hz, 1H), 8.39 (s, 1H), 7.75 (s, 1H), 7.59 (dd, J = 8.8, 2.4 Hz,1H), 7.46 (d, J = 4.76 Hz, 1H), 7.42 (d, J = 2.56 Hz, 1H), 7.35 (d, J =9.0 Hz, 1H), 4.39 (t, J = 5.8 Hz, 2H), 4.23 (t, J = 5.3 Hz, 2H), 3.63(s, 2H), 2.28 (s, 6H), 1.77 (s, 3H) 517

MS (ESI) m/z 592.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.98 (bs, 1H),8.81 (d, J = 4.68 Hz, 1H), 8.41 (s, 1H), 8.00 (d, J = 6.56 Hz, 1H), 7.60(dd, J = 8.76, 2.28 Hz, 1H), 7.47 (d, J = 4.68 Hz, 1H), 7.42 (d, J =2.23 Hz, 1H), 7.37 (d, J = 8.96 Hz, 1H), 4.53 (s, 2H), 4.41 (t, J = 6.24Hz, 2H), 4.26 (t, J = 6.28 Hz, 2H), 2.89 (s, 6H), 1.80 (s, 3H) 518

MS (ESI) m/z 642.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J =4.4 Hz, 1H), 8.45 (s, 1H), 7.49 (m, 5H), 4.63 (bs, 2H), 4.43 (bs, 2H),4.29 (bs, 2H), 2.83 (bs, 6H), 1.86 (s, 3H) 520

MS (ESI) m/z 678.03 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.65 (bs,1H), 8.89 (d, J = 4.12 Hz, 1H), 8.48 (s, 1H), 7.90 (s, 1H), 7.65-7.35(m, 5H), 4.40 (t, J = 5.18 Hz, 2H), 4.23 (t, J = 6.72 Hz, 2H), 3.56 (s,3H), 1.71 (s, 3H) 529

MS (ESI) m/z 638.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.59 (bs,1H), 8.38 (s, 1H), 8.04 (d, J = 8.72 Hz, 1H), 7.77 (d, J = 8.20 Hz, 1H),7.80-7.55 (m, 1H), 7.42-7.40 (m, 2H), 7.35 (d, J = 9.00 Hz, 1H), 4.40(t, J = 4.52 Hz, 2H), 4.25 (t, J = 5.16 Hz, 2H), 2.69 (s, 3H), 2.60-2.20 (merged, 8H), 1.83 (s, 3H) 530

MS (ESI) m/z 623.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.28 (bs,1H), 8.80 (d, J = 4.72 Hz, 1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.62- 7.32(m, 5H), 4.62 (s, 2H), 4.41 (t, J = 4.92 Hz, 2H), 4.26 (t, J = 5.40 Hz,2H), 2.87 (s, 6H), 1.79 (s, 3H) 531

MS (ESI) m/z 640.12 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.40 (bs,1H), 9.88 (bs, 1H), 8.83 (d, J = 4.48 Hz ,1H), 8.34 (s, 1H),7.74-7.35(m, 6H), 4.54 (s, 2H), 4.41 (t, J = 5.6 Hz, 2H), 4.25 (t, J = 5.6 Hz,2H), 2.94 (s, 6H), 1.76 (s, 3H) 532

MS (ESI) m/z 658.20 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (bs,1H), 8.84 (d, J = 3.04 Hz, 1H), 8.28 (s, 1H), 7.60 (bs, 2H), 7.47- 7.35(m, 3H), 4.59 (s, 2H), 4.41 (t, J = 4.92 Hz, 2H), 4.26 (t, J = 4.72 Hz,2H), 2.90 (s, 6H), 1.76 (s, 3H) 533

MS (ESI) m/z 578.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.76 Hz, 1H), 8.37 (s, 1H), 7.67 (d, J = 10.08 Hz, 1H), 7.59-7.56 (dd, J= 2.6, 2.56 Hz, 1H), 7.45 (d, J = 4.64 Hz, 1H), 7.40-7.35 (m, 2H), 5.97(s, 1H), 4.69 (s, 2H), 4.40 (t, J = 4.64 Hz, 2H), 4.21 (t, J = 4.64 Hz,2H), 3.42 (s, 3H), 1.68 (s, 3H) 534

MS (ESI) m/z 594.04. [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.72 Hz, 1H), 8.37 (s, 1H), 7.73 (d, J = 10.16 Hz, 1H), 7.58-7.56 (dd, J= 2.48, 2.28 Hz, 1H), 7.44-7.37 (m, 3H), 5.98 (s, 1H) 4.40 (t, J = 5.30Hz, 2H), 4.20 (t, J = 4.54 Hz, 2H), 3.98 (s, 2H), 2.04 (s, 3H), 1.66 (s,3H) 536

MS (ESI) m/z 601.05 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.72 Hz, 1H), 8.47 (s, 1H), 7.72-7.34 (m, 6H), 4.39 (t, J = 6.4 Hz, 2H),4.22 (t, J = 6.4 Hz, 2H), 1.71 (s, 3H) 537

MS (ESI) m/z 615.03 [M − 1]; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.5 Hz, 1H), 8.49 (s, 1H), 7.76-7.33 (m, 6H), 4.88 (t, J = 5.4 Hz, 2H),4.23 (t, J = 6.1 Hz, 2H), 1.69 (s, 3H) 538

MS (ESI) m/z 608.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.39 (bs,1H), 8.85 (d, J = 4.7 Hz, 1H), 8.43 (s, 1H), 7.83-7.33 (m, 6H), 4.39(bs, 2H), 4.25 (bs, 2H), 1.72 (s, 3H) 539

MS (ESI) m/z 633.2 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 13.49 (bs, 1H),8.84 (d, J = 4.8 Hz, 1H), 8.49 (s, 1H), 7.75-7.24 (m, 7H), 4.39 (t, J =4.16 Hz, 2H), 4.24 (t, J = 5.0 Hz, 2H), 1.70 (s, 3H) 540

MS (ESI) m/z 651.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.76 Hz, 1H), 8.48 (s, 1H), 7.78-7.48 ( m, 4H), 7.44 (d, J = 2.6 Hz,1H), 7.36 (d, J = 9.0 Hz, 1H), 4.39 (t, J = 4.56 Hz, 2H), 4.29 (t, J =4.52 Hz, 2H), 1.70 (s, 3H) 541

MS (ESI) m/z 649.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.76, 1H), 8.47 (s, 1H), 7.93 (s, 1H), 7.93 (s, 1H), 7.59 (dd, J = 8.88,2.52 ,1H), 7.48-6.83 (m, 5H), 4.38 (t, J = 5.48 Hz, 2H), 4.22 (t, J =4.84, 2H), 1.73 (s, 3H) 542

MS (ESI) m/z 635.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.33 (bs,1H), 8.83 (d, J = 4.76 Hz, 1H), 8.367 (s, 1H), 7.76 (d, J = 1.32, 1H),7.58 (dd, J = 2.6 Hz, J = 8.88 Hz, 1H), 7.48 (d, J = 4.76 Hz, 1H), 7.43(d, J = 1.76 Hz, 1H) 7.34 (d, J = 8.92 Hz, 1H), 4.39 (s, 2H), 4.23 (s,2H), 1.74 (s, 3H) 543

MS (ESI) m/z 626.11 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.76 Hz, 1H), 8.34 (s, 1H), 7.76 (s, 1H), 7.60 (dd, J = 8.80, 2.44 Hz,1H), 7.49 (d, J = 4.68 Hz, 1H), 7.43 (d, J = 2.48 Hz, 1H), 7.35 (d, J =8.96 Hz, 1H) 4.40 (t, J = 4.32 Hz, 2H), 4.25 (t, J = 4.12 Hz, 2H), 1.74(s, 3H) 544

MS (ESI) m/z 626.11 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.85 (d, J =4.76 Hz, 1H), 8.34 (s, 1H), 7.76 (s, 1H), 7.60 (dd, J = 8.80, 2.44 Hz,1H), 7.49 (d, J = 4.68 Hz, 1H), 7.43 (d, J = 2.48 Hz, 1H), 7.35 (d, J =8.96 Hz, 1H) 4.40 (t, J = 4.32 Hz, 2H), 4.25 (t, J = 4.12 Hz, 2H), 1.74(s, 3H) 545

MS (ESI) m/z 601.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.76 Hz, 1H), 8.44 (s, 1H), 7.69 (d, J = 10.76 Hz, 1H), 7.60 (dd, J =2.64, 8.76 Hz, 1H), 7.48 (d, J = 4.68 Hz, 1H), 7.42 (d, J = 2.68 Hz,1H), 7.41 (t, J = 71.52 Hz, 1H), 7.35 (d, J = 8.92 Hz, 1H), 4.38 (t, J =4.44 Hz, 2H), 4.23 (t, J = 4.44 Hz, 2H), 1.77 (s, 3H) 546

MS (ESI) m/z 617.13 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.68 Hz, 1H), 8.41 (s, 1H), 7.92 (s, 1H), 7.60 (dd, J = 2.60, 9.52 Hz,1H), 7.50 (d, J = 4.56 Hz, 1H), 7.42 (d, J = 1.84 Hz, 1H), 7.36 (bs,1H), 7.35 (t, J = 71.96 Hz, 1H), 4.39 (t, J = 5.08 Hz, 2H), 4.23 (t, J =5.08 Hz, 2H), 1.76 (s, 3H) 547

MS (ESI) m/z 608.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.25 (bs,1H), 8.86-8.79 (m, 1H), 8.60-8.49 (m, 2H), 7.72-7.33 (m, 5H), 4.46-4.36(m, 2H), 4.33-4.24 (m, 2H), 1.94 (s, 3H) 548

MS (ESI) m/z 633.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.76 Hz, 1H), 8.57 (s, 1H), 8.04 (s, 1H), 7.81- 7.35 (m, 6H), 4.41 (t, J= 5.04 Hz, 2H), 4.25 (t, J = 4.84 Hz, 2H), 1.81 (s, 3H) 550

MS (ESI) m/z 635.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.8 Hz, 1H), 8.41 (s, 1H), 8.00 (s, 1H), 7.60 (dd, J = 2.52 Hz, 8.84 Hz,1H), 7.50 (d, J = 4.76, 1H), 7.45 (d, J = 2.48, 1H), 7.36 (d, J = 8.96Hz, 1H), 4.40 (t, J = 4.48 Hz, 2H), 4.24 (t, J = 4.32 Hz, 2H), 1.75 (s,3H) 551

MS (ESI) m/z 650.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.76 Hz, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.59 (dd, J = 8.92, 2.40 Hz,1H), 7.48-7.19 (m, 4H), 4.40 (t, J = 5.6 Hz, 2H), 4.25 (t, J = 5.6 Hz,2), 1.76 (s, 3H). 552

MS (ESI) m/z 658.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =4.7Hz, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.62-7.59 (m, 1H), 7.46 (t, J =4.2 Hz, 2H), 7.37 (d, J = 8.9 Hz, 1H), 4.5 (bs, 2H), 4.41 (t, J = 4.3Hz, 2H), 4.26 (t, J = 4.3 Hz, 2H), 2.86 (s, 6H), 1.80 (s, 3H). 557

MS (ESI) m/z 579.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.96 (bs,1H), 8.73 (d, J = 4.7 Hz, 1H), 8.66 (s, 1H), 8.13 (d, J = 9.7 Hz, 1H),7.76 (d, J = 9.0 Hz, 1H), 7.68 (m, 2H), 7.53 (d, J = 4.7 Hz, 1H), 7.37(t, J = 53.7 Hz, 1H), 4.88 (s, 2H), 2.22 (s, 3H) 566

MS (ESI) m/z 676.15 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.93 (bs,1H), 8.06 (d, J = 9.72 Hz, 1H), 7.60 (dd, J = 8.80, 2.40 Hz, 1H),7.48-7.22 (m, 4H), 4.43 (t, J = 4.6 Hz, 2H), 4. 28 (t, J = 4.8 Hz, 2H),3.5 (s, 3H), 2.69 (s, 3H), 1.94 (s, 3H) 567

MS (ESI) m/z 644.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H),8.48 (s, 1H), 7.73 (dd, J = 7.88, 10.80 Hz, 1H), 7.60 (dd, J = 2.44,8.88 Hz, 1H), 7.48 (s, 1H), 7.40 (d, J = 2.60 Hz, 1H), 7.36 (d, J = 9.2Hz, 1H), 4.41 (t, J = 5.12 Hz, 2H). 4.23 (t, J = 4.28 Hz, 2H), 3.57 (s,3H), 2.71 (s, 3H), 1.80 (s, 3H) 570

MS (ESI) m/z 676.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.34 (bs,1H), 8.80 (s, 1H), 8.12 (d, J = 10.0 Hz, 1H), 7.56 (dd, J = 8.8 Hz 2.80Hz, 1H), 7.49-7.22 (m, 4H), 4.38 (t, J = 5.20 Hz, 2H), 4.245 (t, J =4.40 Hz, 2H), 2.63 (s, 3H). 1.98 (s, 3 H), 1.75 (s, 3H) 572

MS (ESI) m/z 531.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =4.72 Hz, 1H), 8.39 (s, 1H), 7.83 (d, J = 8.64 Hz, 1H), 7.58 (d, J = 8.64Hz, 2H), 7.48 (d, J = 4.84 Hz, 1H), 7.42 (d, J = 2.52 Hz, 1H), 7.35 (d,J = 9.0 Hz, 1H), 4.41-4.38 (m, 2H), 4.24-4.23 (m, 2H), 2.60 (s, 3H),1.79 (s, 3H) 573

MS (ESI) m/z 531.18 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.04 Hz ,1H), 8.30 (s, 1H), 7.79 (s, 1H), 7.58 (d, J = 8.88 Hz, 1H),7.46 (m, 2H), 7.41 (m, 2H), 7.35 (d, J = 9.08 Hz, 1H), 4.35 (s, 2H),4.19 (s, 2H), 2.49 (s, 3H), 1.81 (s, 3H) 574

MS (ESI) m/z 531.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.26 (bs, 1H),8.80 (d, J = 4.68 Hz, 1H), 8.43 (s, 1H), 7.82 (d, J = 7.56, 1H), 7.55(d, J = 7.68, 1H), 7.59 (dd, J = 2.44, 2.48 Hz,1H), 7.46 (d, J = 4.68Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.96 Hz, 1H), 4.42 (s,2H), 4.23 (s, 2H), 3.38 (s, 3H), 1.815 (s, 3H) 575

MS (ESI) m/z 654.14 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ, 8.27 (s, 1H),8.04-7.67 (3, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.59-7.56 (m, 1H), 7.42 (m,1H), 7.35 (d, J = 9.2 Hz, 1H), 7.10 (s, 1H), 4.39 (t, J = 4.8 Hz, 2H),4.24 (t, J = 5.6 Hz, 2H), 3.07(t, J = 7.2 Hz, 2H), 2.58 (t, J = 7.2 Hz,2H), 2.22 (s, 6H), 1.75 (s, 3H) 576

MS (ESI) m/z 601.30 [M + 1]+., 1H-NMR (400 MHz, DMSO-d6) δ 12.96 (bs,1H), 7.90 (d, J = 8.44 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.44 Hz,1H),7.48 (dd, J = 2.44, 8.76 Hz,1H), 7.27-7.22 (m, 3H), 7.10 (d, J =7.28 Hz, 1H), 4.32 (t, J = 4.8 Hz, 2H), 4.20 (t, J = 4.8 Hz, 2H), 2.86(s, 6H), 2.68 (s, 3H), 1.72 (s, 3H) 577

MS (ESI) m/z 637.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.16-7.87 (m,3H), 7.33 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.53 (dd, J =2.6, 8.8 Hz, 1H), 7.37-7.30 (m, 3H), 4.31 (t, J = 5.6 Hz, 2H), 4.17 (t,J = 5.6 Hz, 2H), 3.09 (t, J = 6.9 Hz, 2H), 2.56 (t, J = 6.8 Hz, 2H),2.32 (s, 6H), 1.73 (s, 3H) 578

MS (ESI) m/z 655.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H),7.88-7.85 (m, 2H), 7.68 (d, J = 8.48 Hz, 1H), 7.54 (dd, J = 2.60, 8.88Hz, 1H), 7.41-7.38 (m, 2H), 7.30 (d, J = 8.92 Hz, 1H), 4.34 (t, J = 4.36Hz, 2H), 4.19 (t, J = 4.96 Hz, 2H), 3.07 (t, J = 7.20 Hz, 2H), 2.65-2.62 (m, 2H), 2.27 (s, 6H), 1.66 (s, 3H) 579

MS (ESI) m/z 597.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.66 (bs,1H), 8.43 (s, 1H), 7.84 (s, 1H), 7.71-7.33 (m, 6H), 4.39-4.37 (m, 2H),4.23-4.21 (m, 2H), 2.70 (s, 3H), 1.81 (s, 3H) 580

MS (ESI) m/z 674.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.07 (bs,1H), 8.44 (s, 1H), 7.85 (s, 1H), 7.71 to 7.41 (m, 4H), 7.36 to 7.32 (m,2H), 4.4 (bs, 2H), 4.21 (bs, 2H), 3.56 (s, 3H), 2.71 (s, 3H), 1.79 (s,3H) 581

MS (ESI) m/z 674.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.07 (bs,1H), 8.44 (s, 1H), 7.85 (s, 1H), 7.71 to 7.41 (m, 4H), 7.36 to 7.32 (m,2H), 4.4 (bs, 2H), 4.21 (bs, 2H), 3.56 (s, 3H), 2.71 (s, 3H), 1.79 (s,3H) 582

MS (ESI) m/z 599.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (bs,1H), 8.37 (s, 1H), 7.89 (s, 1H), 7.60 (dd, J = 1.88 Hz, 8.84 Hz, 1H),7.41 (s, 2H), 7.35 (d, J = 8.84 Hz, 1H), 4.40-4.38 (m, 2H), 4.24-4.22(m, 2H), 2.70 (s, 3H), 1.82 (s, 3H) 583

MS (ESI) m/z 615.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.5 (bs, 1H),8.41 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 9.08, 1H), 7.59(dd, J = 2.44, 8.80, 1H), 7.42-7.41 (m, 1H), 7.35 (d, J = 8.96, 1H),4.39 (t, J = 5.08 Hz, 2H), 4.24 (t, J = 4.52, 2H), 2.69 (s, 3H), 1.83(s, 3H) 584

MS (ESI) m/z 602.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.74 (bs, 1H),8.33 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H),7.61-7.58 (m, 1H), 7.41-7.35 (m, 3H), 4.41 (t, J = 4.8 Hz, 2H), 4.26 (t,J = 5.6 Hz, 2H), 3.41 (t, J = 9.6 Hz, 2H), 3.37 (t, J = 3.2 Hz, 2H),2.91 (s, 6H), 2.70 (s, 3H), 1.87 (s, 3H) 585

MS (ESI) m/z 615.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.68 (bs,1H), 8.43 (s, 1H), 7.60-7.55 (m, 2H), 7.54 (t, J = 71.72 Hz, 1H), 7.43(s, 1H), 7.40 (d, J = 4.00 Hz, 1H), 7.34 (d, J = 9.04 Hz, 1H), 4.38 (t,J = 4.68 Hz, 2H), 4.23 (t, J = 4.60 Hz, 2H), 2.71 (s, 3H), 1.78 (s, 3H)586

MS (ESI) m/z 615.07 [M + 1]+. 1H-NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H),7.83 (s, 1H), 7.63-7.34 (m, 5H), 4.40 (t, J = 4.0 Hz, 2H), 4.25 (t, J =4.4 Hz, 2H), 2.70 (s, 3H), 1.83 (s, 3H) 587

MS (ESI) m/z 599.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.5 (s, 1H),8.44 (s, 1H), 8.04 (d, J = 9.24 Hz, 1H), 7.62-7.58 (m, 1H), 7.47-7.21(m, 4H), 4.41 (bs, 2H), 4.28 (bs, 2H), 2.69 (s, 3H), 1.94 (s, 3H) 588

MS (ESI) m/z 581.17 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H),8.15 (d, J = 9.32 Hz, 1H), 7.59 (dd, J = 2.44, 8.88 Hz, 1H), 7.40-7.35(m, 3H), 4.41 (t, J = 6.24 Hz, 2H), 4.27 (t, J = 5.44 Hz, 2H), 2.70 (s,3H), 1.93 (s, 3H) 592

MS (ESI) m/z 668.20 [M + 1]+; UPLC: 92.22%; 1H NMR (400 MHz, DMSO-d6) 6:8.32 (s, 1H), 7.78-7.33 (m, 6H), 4.38 (t, J = 4.7 Hz, 2H), 4.22 (t, J =4.3 Hz, 2H), 3.06-3.04 (m, 2H), 2.76-2.69 (m, 5H), 2.23 (s, 6H), 1.82(s, 3H) 593

MS (ESI) m/z [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.01(d, J = 9.60 Hz, 1H), 7.88 (s, 1H), 7.67 (dd, J = 8.96, 2.52 Hz, 1H),7.51 (d, J = 2.52 Hz, 1H), 7.49-7.22 (m, 2H), 4.46 (t, J = 4.84 Hz, 2H),4.33 (t, J = 4.52 Hz, 2H), 2.94 (s, 3H), 2.07 (s, 3H) 594

MS (ESI) m/z 669 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H),8.45 (s, 1H), 8.01 (d, J = 9.76 Hz, 1H), 7.59 (dd, J = 8.88, 2.40, 1H),7.47-7.20 (m, 4H), 4.40 (t, J = 4.36 Hz, 2H), 4.28 (t, J = 4.76 Hz, 2H),3.11 (bs, 6H), 2.67 (s, 3H), 1.99 (s, 3H) 596

MS (ESI) m/z 532.14 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H),8.42 (s, 1H), 8.37 (s, 1H), 7.59 (dd, J = 8.84 Hz, 2.56 Hz, 1H), 7.41(t, J = 4.44 Hz, 2H), 7.33 (d, J = 8.92, 1H), 4.38 (t, J = 6.12 Hz, 2H),4.27 (t, J = 6.2 Hz, 2H), 2.70 (s, 3H), 1.86 (s, 3H) 598

MS (ESI) m/z 608.90 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H),8.86 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 7.60 (dd, J = 7.24 Hz, 2.64Hz,1H), 7.45 (s, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 8.96 Hz, 1H),4.26 (t, J = 6.04 Hz, 2H), 4.26 (t, J = 4.52 Hz, 2H), 3.59 (s, 3H), 2.71(s, 3H), 1.88 (s, 3H) 599

MS (ESI) m/z 526.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.02 (bs, 1H),8.45 (bs, 2H), 7.74 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.40 (bs, 1H),4.88 (s, 2H), 2.66 (s, 3H), 2.19 (s, 3H), 606

MS (ESI) m/z 650.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.75 (bs,1H), 9.50-9.30 (m, 1H), 8.29 (s, 1H), 7.64 (s, 1H), 7.60 (dd, J = 8.92,2.56 Hz, 1H), 7.45 (s, 1H), 7.40 (d, J = 2.56 Hz, 1H), 7.36 (d, J = 9.0Hz, 1H), 4.40 (t, J = 5.04 Hz, 2H), 4.24 (t, J = 4.48 Hz, 2H), 3.28-3.15(m, 2H), 2.93 (t, J = 7.64 Hz, 2H), 2.83 (d, J = 4.60, 6H), 2.72 (s,3H), 2.18-2.07 (m, 2H), 1.84 (s, 3H) 607

MS (ESI) m/z 668.24 [M + 1]+; UPLC: 97.83%; 1H NMR (400 MHz, DMSO-d6) δ8.25 (s, 1H), 7.66 (s, 1H), 7.58 (dd, J = 8.68 Hz, J = 2.36 Hz, 1H),7.47-7.12 (m, 4H), 4.41 (t, J = 4.5 Hz, 2H), 4.24 (t, J = 4.3 Hz, 2H),3.46 (t, J = 6.0 Hz, 2H), 3.18 (t, J = 8.0 Hz, 2H), 2.89 (s, 6H), 2.70(s, 3H), 1.81 (s, 3H) 608

MS (ESI) m/z 620.22 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H),7.81 (d, J = 10.8 Hz, 1H), 7.58 (dd, J = 2.36 Hz, 9.0 Hz, 1H), 7.39-7.35 (m, 3H), 4.40 (t, J = 4.88 Hz, 2H), 4.25 (t, J = 4.44 Hz, 2H), 3.07(t, J = 7.36 HZ, 2H), 2.69 (s, 5H), 2.28 (s, 6H), 1.94 (s, 3H) 609

MS (ESI) m/z 636.04 [M + 1]+: 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H),7.74 (s, 1H), 7.59-7.57 (m, 1H), 7.40- 7.33 (m, 3H), 4.38 (t, J = 5.0Hz, 2H), 4.22 (t, J = 3.92 Hz, 2H), 3.50 (s, 2H), 3.21 (t, J = 7.96 Hz,2H) 2.69 (s, 3H), 2.26 (s, 6H), 1.84 (s, 3H) 611

MS (ESI) m/z 614.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H),7.61 (dd, J1 = 2.5 Hz, J2 = 8.8 Hz, 1H), 7.48 (s, 1H), 7.42 (s, 1H),7.38(s, 1H), 7.36 (S, 1H), 4.40 (S, 2H), 4.39-4.30 (m, 1H),4.20 (s, 2H),3.61-3.54 (m, 2H), 3.45-3.20 (m, 2H), 2.9 (s, 6H), 2.71 (s, 3H), 1.93(s, 3H) 612

MS (ESI) m/z 614.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.63 (bs, 1H),9.72 (bs, 1H), 8.16 (s, 1H), 7.61-7.59 (m, 2H), 7.44-7.36 (m, 3H),5.19-5.08 (m, 1H), 4.50-4.35 (m, 2H), 4.35-4.18 (m, 2H), 3.23-3.07 (m,2H), 2.93-2.73 (m, 6H), 2.73 (s, 3H), 1.90 (s, 1H) 613

MS (ESI) m/z 614.24 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H),7.59-7.56 (dd, J = 2.52, 2.56 Hz, 1H), 7.48 (s, 1H), 7.40 (d, J = 2.4Hz, 1H), 7.36-7.33 (m, 2H), 4.49 (t, J = 7.52 Hz, 1H), 4.41-4.19 (m,4H), 3.14-2.98 (m, 2H), 2.67. (s, 3H), 2.20 (s, 6H), 2.12-2.05 (m, 2H),1.89 (s, 3H) 618

MS (ESI) m/z 696.40 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.57 (bs,1H), 8.41 (s ,1H), 7.90 (s, 1H), 7.60-7.57 (dd, J = 2.25, 8.8 Hz, 1H),7.41-7.32 (m, 4H), 4.39 (t, J = 5.28 Hz, 2H), 4.23 (t, J = 5.28 Hz, 2H),3.71 (s, 2H), 2.68 (s, 3H), 2.11 (s, 3H), 1.82 (s, 3H), 1.15 (s, 9H) 619

MS (ESI) m/z 682.24 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.83 (bs, 1H),8.36 (s ,1H), 8.01 (s, 1H), 7.69-7.33 (m, 5H), 4.42 (t, J = 4.72 Hz,2H), 4.28 (m, 4H), 2.72 (s, 3H). 1.92 (s, 3H). 1.42 (s, 9H) 620

MS (ESI) m/z 631.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.76 Hz, 1H), 8.24 (s, 1H), 7.67 (s, 1H), 7.61 (dd, J = 2.64, J = 8.88Hz, 1H), 7.47 (d, J = 4.80 Hz, 1H), 7.43 (d, J = 2.64 Hz, 1H), 7.35 (d,J = 9.04 Hz, 1H), 4.65 (s, 2H), 4.39 (t, J = 4.48 Hz, 2H), 4.21 (t, J =4.32 Hz, 2H), 2.87 (s, 6H), 1.77 (s, 3H) 621

MS (ESI) m/z 634.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =4.74 Hz, 1H), 8.25 (s, 1H), 7.65 (s, 1H), 7.60 (dd, J = 8.84, 2.48 Hz,1H), 7.48 (d, J = 4.72 Hz, 1H), 7.43 (d, J = 2.48, 1H), 7.35 (d, J =8.96, 1H), 4.55 (2H), 4.39 (bs, 2H), 4.24 (bs, 2H), 2.92 (s, 6H), 1.78(s, 3H). 622

MS (ESI) m/z 617.93 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J =4.72 Hz, 1H), 8.60 (s, 1H), 8.09 (s, 1H), 7.76 (d, J = 8.92 Hz, 1H),7.69-7.65 (m, 2H), 7.54-7.38 (m, 2H), 4.90 (s, 2H), 4.63 (bs, 2H), 2.88(s, 6H), 2.14 (s, 3H) 623

MS (ESI) m/z 636.00 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H),8.59 (s, 1H), 8.06 (s, 1H), 7.76 (d, J = 8.92, 1H), 7.68 (d, J = 1.8 Hz,2H), 7.53 (s, 1H), 4.87 (s, 2H), 3.70 (s, 2H), 2.23 (s, 6H), 2.12 (s,3H) 625

MS (ESI) m/z 512.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.0 (s, 1H),8.74 (d, J = 4.8 Hz, 1H), 8.6 (s, 1H), 8.43 (s, 1H), 7.75 (d, J = 8.9Hz, 1H), 7.68 (m, 2H), 7.51 (d, J = 4.6 Hz, 1H), 4.87 (s, 2H), 2.17 (s,3H) 626

MS (ESI) m/z 634.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.14 (bs,1H), 8.74 (d, J = 4.72 Hz, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 7.77- 7.60(m, 3H), 7.57-7.24 (m, 2H), 4.88 (s, 2H), 4.53 (s, 2H), 2.88 (s, 6H),2.16 (s, 3H) 627

MS (ESI) m/z 594.95 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H),7.80 (s, 1H), 7.60 (dd, J = 2.36, J = 2.52, 1H), 7.20-7.40 (m, 4H), 4.40(bs, 2H), 4.25 (bs, 2H), 2.68 (s, 3H), 2.65 (s, 3H), 1.88 (s, 3H) 628

MS (ESI) m/z 559.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H),7.59 (dd, J = 2.6 Hz, 2.56 Hz, 1H), 7.44 (s, 1H), 7.35-7.39 (m, 3H),4.39 (s, 2H), 4.23 (s, 2H), 2.70 (s, 3H), 2.51 (s, 3H), 2.437 (s, 3H),1.9 (s, 3H) 635

MS (ESI) m/z 656.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.48 (s, 1H),8.38 (s, 1H), 7.92 (s, 1H), 7.59 (dd, J = 8.88, 2.52 Hz, 1H), 7.40-7.34(m, 3H), 4.39 (t, J = 4.6 Hz, 2H), 4.25 (t, J = 4.6 Hz, 2H), 3.68 (s,2H), 2.69 (s, 3H), 2.22 (s, 6H), 1.90 (s, 3H) 639

MS (ESI) m/z 667.15 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H),7.74 (bs, 1H), 7.59 (dd, J = 2.46 Hz, 8.88 Hz, 1H), 7.49-7.31 (m, 4H),4.39 (bs, 2H), 4.23 (bs, 2H), 3.58 (bs, 2H), 3.02 (q, J = 7.52 Hz, 2H),2.25( s, 6H), 1.78 (s, 3H), 1.35 (t, J = 7.24 Hz, 3H) 646

MS (ESI) m/z 693.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ, 9.41 (bs,1H), 8.33 (s, 1H), 7.86 (s, 1H), 7.69-7.35 (m, 5H), 4.41 (t, J = 6.4 Hz,2H), 4.26 (t, J = 6.4 Hz, 2H), 4.00 (s, 2H), 3.41 (d, J = 12.0 Hz, 2H),3.02-2.94 (m, 4H), 2.79 (d, J = 3.6 Hz, 3H), 2.64 (s, 3H),2.49 (bs, 2H),1.85 (s, 3H) 647

MS (ESI) m/z 642.99 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H),7.92 (d, J = 8.52 Hz, 1H), 7.64 (d, J = 8.48 Hz, 1H), 7.58 (dd, J =8.84, 2.44 Hz, 1H), 7.41-7.34 (m, 3H), 4.42-4.37 (m, 2H), 4.27-4.21 (m,2H), 3.75 (s, 3H), 2.68 (s, 3H), 2.50-2.30 (m, 6H), 2.21-2.16 (s, 4H),1.85 (s, 3H) 648

MS (ESI) m/z 599.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H),7.77 (d, J = 10.56 Hz, 1H), 7.60 (m, 1H), 7.40-7.35 (m, 3H), 4.41 (bs,2H), 4.26 (bs, 2H), 2.69 (s, 3H), 2.58 (s, 3H), 1.98 (s, 3H) 650

MS (ESI) m/z 602.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H),7.86 (s, 1H), 7.61 (dd, J = 8.92 Hz, 2.48 Hz, 1H), 7.43 (s, 1H), 7.41(d, J = 2.52, 1H), 7.38 (d, J = 9.00 Hz, 1H), 4.54 (s, 2H), 4.43 (t, J =5.72, 2H), 4.27 (t, J = 4.2 Hz, 2H), 2.87 (s, 6H), 2.71 (s, 3H), 2.67(s, 3H), 1.95 (s, 3H) 651

MS (ESI) m/z 721.31 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =8.80 Hz, 1H), 8.47 (s ,1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.61 (dd, J =2.52, 8.84 Hz 1H), 7.47-7.19 (m, 4H), 4.41-4.40 (m, 6H), 4.21 (s, 2H),4.10 (s, 3H), 2.67 (s, 3H). 1.82 (s, 3H) 653

MS (ESI) m/z 642.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 8.76-8.73 (m,2H), 8.45 (s, 1H), 8.03 (d, J = 7.84 Hz, 1H), 7.86 (s,1H), 7.67- 7.64(m, 1H), 7.59 (dd, J = 8.8, 2.44 Hz, 1H), 7.45-7.40 (m, 2H), 7.36 (d, J= 8.96 Hz, 1H), 4.40 (t, J = 4.28 Hz, 2H), 4.26 (t, J = 3.76 Hz, 2H),2.72 (s, 3H), 1.90 (s, 3H) 654

MS (ESI) m/z 608.35 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 9.20 (bs, 1H),8.74 (bs ,1H), 8.45 (d, J = 7.96 Hz, 1H), 8.39 (s, 1H), 8.32 (s, 1H),8.00 (s, 1H), 7.66 (m, 1H), 7.61-7.57 (dd, J = 2.26, 8.56 Hz, 1H),7.45(s, 1H), 7.41 (d, J = 2.48 Hz, 1H), 7.38 (d, J = 8.96 Hz, 1H), 4.44 (t,J = 5.20 Hz, 2H), 4.26 (t, J = 4.60 2H), 2.71 (s, 3H), 1.84 (s, 3H), 657

LCMS (ESI) m/z 552.3 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.70 (dd, J =8.7, 1.1 Hz, 1H), 8.62 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H),8.16 (s, 1H), 8.07 (dd, J = 7.4, 1.1 Hz, 1H), 7.95 (dd, J = 8.3, 7.4 Hz,1H), 7.55 (dd, J = 8.9, 2.7 Hz, 1H), 7.38 (d, J = 1Hz, 1H), 7.36 (d, J =5.2 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.16-7.06 (m, 2H), 7.01-6.92 (m,1H), 4.56-4.50 (m, 4H) 658

LCMS (ESI) m/z 529.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H),9.10 (s, 1H), 8.62-8.51 (m, 2H), 8.25 (dd, J = 8.0, 1.3 Hz, 1H), 8.08(s, 1H), 7.95 (ddd, J = 8.3, 7.2, 1.4 Hz, 1H), 7.80 (ddd, J = 8.1, 7.3,1.1 Hz, 1H), 7.56 (dd, J = 9.0, 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H),7.33-7.26 (m, 2H), 4.61 (t, J = 5.2 Hz, 2H), 4.50 (t, J = 5.1 Hz, 2H)659

LCMS (ESI) m/z 543.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.20-10.15(m, 1H), 9.83 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 8.36 (d, J = 8.5 Hz,1H), 8.21 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.9, 2.7 Hz,1H), 7.43-7.30 (m, 2H), 4.42 (d, J = 5.1 Hz, 1H), 4.30 (t, J = 4.9 Hz,1H), 2.44-2.38 (m, 1H), 1.94 (s, 3H) 665

LCMS (ESI) m/z 592.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J =4.8 Hz, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.62- 7.56 (m, 2H), 7.46 (d, J = 4.8 Hz, 1H), 3.76 (s, 3H),3.49 (s, 2H), 2.03 (s, 4H) 669

LCMS (ESI) m/z 626.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.73-8.63 (m,2H), 8.35 (s, 1H), 7.68-7.53 (m, 3H), 7.47 (d, J = 4.8 Hz, 1H), 3.77 (s,1H), 2.05 (d, J = 4.3 Hz, 1H), 2.04 (s, 1H) 671

LCMS (ESI) m/z 558.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.23 (d, J =0.7 Hz, 1H), 9.92 (d, J = 1.5 Hz, 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.28(s, 1H), 8.09 (dd, J = 8.6, 0.7 Hz, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H),7.47-7.34 (m, 3H), 4.46 (s, 5H), 4.34 (s, 5H), 2.65 (s, 3H), 2.04 (s,3H) 676

LCMS (ESI) m/z 673.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H),8.10 (s, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.42-7.35 (m, 2H), 7.31(d, J = 9.0 Hz, 1H), 4.35 (t, J = 5.1 Hz, 2H), 4.19 (t, J = 4.9 Hz, 2H),3.19 (m, 4H), 2.88 (d, J = 4.1 Hz, 3H), 2.67 (s, 3H), 1.75 (s, 3H) 677

LCMS (ESI) m/z 673.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H),8.31 (s, 1H), 8.09 (s, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.42-7.35(m, 2H), 7.31 (d, J = 9.0 Hz, 1H), 4.35 (t, J = 5.0 Hz, 2H), 4.19 (d, J= 10.1 Hz, 1H), 3.58 (d, J = 11.8 Hz, 4H), 3.29-3.13 (m, 4H), 2.88 (d, J= 3.4 Hz, 3H), 2.67 (s, 3H), 1.75 (s, 3H) 678

LCMS (ESI) m/z 605.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H),7.66-7.51 (m, 1H), 7.47-7.36 (m, 1H), 7.37-7.27 (m, 1H), 4.52 (d, J =13.9 Hz, 1H), 4.33 (t, J = 5.1 Hz, 1H), 4.16 (t, J = 5.1 Hz, 1H), 3.54(d, J = 11.8 Hz, 1H), 3.20 (d, J = 13.0 Hz, 1H), 3.18-3.03 (m, 1H), 2.84(d, J = 3.6 Hz, 2H), 2.67 (s, 1H), 1.73(s, 1H) 679

LCMS (ESI) m/z 550.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H),7.62-7.52 (m, 2H), 7.43 (d, J = 2.7 Hz, 1H), 7.40-7.30 (m, 2H), 7.19 (d,J = 9.2 Hz, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.18 (t, J = 5.0 Hz, 2H),3.12 (s, 6H), 2.70 (s, 3H), 1.73 (s, 3H) 680

LCMS (ESI) m/z 609.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H),8.16 (s, 1H), 7.56 (dd, J = 8.9, 2.6 Hz, 1H), 7.45-7.38 (m, 2H), 7.33(d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.24 (t, J = 5.1 Hz, 2H),4.11 (s, 1H), 2.67 (s, 3H), 1.96 (s, 3H (m, 2H), 7.43 (d, J = 2.7 Hz,1H), 7.40-7.30 (m, 2H), 7.19 (d, J = 9.2 Hz, 1H), 4.36 (t, J = 5.0 Hz,2H), 4.18 (t, J = 5.0 Hz, 2H), 3.12 (s, 6H), 2.70 (s, 3H), 1.73 (s, 3H)681

LCMS (ESI) m/z 650.7 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H),8.00 (s, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H),7.71-7.63 (m, 2H), 7.54 (d, J = 7.7 Hz, 1H), 7.48 (s, 1H), 7.44 (d, J =7.8 Hz, 1H), 4.86 (s, 2H), 2.64 (s, 3H), 2.56 (s, 3H), 2.17 (s, 3H) 682

LCMS (ESI) m/z 653.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H),8.75 (d, J = 4.8 Hz, 1H), 8.60 (s, 1H), 8.29 (s, 1H), 7.75 (d, J = 9.2Hz, 1H), 7.71-7.65 (m, 2H), 7.54 (d, J = 4.8 Hz, 1H), 4.86 (s, 2H), 3.64(dd, J = 24.2, 12.1 Hz, 5H), 3.30 (d, J = 13.5 Hz, 7H), 2.92 (s, 3H),2.12 (s, 3H) 683

LCMS (ESI) m/z 670.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.89 (t, J =7.8 Hz, 1H), 7.78 (s, 1H), 7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.45-7.35 (m,4H), 7.33 (d, J = 9.0 Hz, 1H), 4.38 (t, J = 5.0 Hz, 2H), 2.68 (s, 3H),2.53 (d, J = 11.1 Hz, 6H), 1.93 (s, 3H) 685

LCMS (ESI) m/z 546.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H),7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.45- 7.38 (m, 3H), 7.36 (d, J = 9.0 Hz,1H), 4.39 (d, J = 5.1 Hz, 2H), 4.26 (d, J = 5.1 Hz, 2H), 2.71 (s, 3H),2.64 (s, 3H), 1.90 (s, 3H) 688

LCMS (ESI) m/z 656.1, 658.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.44(s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.55 (s, 1H), 7.43-7.38 (m,2H), 7.36 (d, J = 9.0 Hz, 1H), 5.03 (t, J = 12.6 Hz, 4H), 4.38 (m, 2H),4.19 (m, 2H), 2.72 (s, 3H), 1.83 (s, 3H) 689

LCMS (ESI) m/z 688.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J =0.4 Hz, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.51 (s, 1H), 7.42 (s, 1H),7.41 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.84 (t, J = 9.3 Hz,2H), 4.63 (dd, J = 9.6, 5.0 Hz, 2H), 4.37 (t, J = 5.1 Hz, 2H), 4.18 (t,J = 5.1 Hz, 2H), 3.67 (d, J = 9.1 Hz, 0H), 2.73 (s, 3H), 1.81 (s, 3H)690

LCMS (ESI) m/z 670.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J =0.4 Hz, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.51 (s, 1H), 7.42 (s, 1H),7.41 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 4.84 (t, J = 9.3 Hz,2H), 4.63 (dd, J = 9.6, 5.0 Hz, 2H), 4.37 (t, J = 5.1 Hz, 2H), 4.18 (t,J = 5.1 Hz, 2H), 3.67 (d, J = 9.1 Hz, 0H), 2.73 (s, 3H), 1.81 (s, 3H)691

LCMS (ESI) m/z 648.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.56 (dd, J =8.9, 2.7 Hz, 1H), 7.45-7.27 (m, 3H), 4.33 (t, J = 5.0 Hz, 2H), 4.28 (bs,2H), 4.14 (t, J = 5.0 Hz, 2H), 2.69 (s, 2H), 1.76 (s, 2H), 1.27 (s, 3H)692

LCMS (ESI) m/z 580.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H),7.60-7.51 (m, 2H), 7.43-7.34 (m, 2H), 7.31 (d, J = 9.0 Hz, 1H), 6.45 (s,2H), 4.33 (t, J = 5.0 Hz, 2H), 4.15 (t, J = 4.9 Hz, 2H), 2.67 (s, 3H),1.69 (s, 3H) 693

LCMS (ESI) m/z 567.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H),8.10 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.59 (dd, J = 8.9,2.7 Hz, 1H), 7.44-7.40 (m, 2H), 7.35 (d, J = 9.0 Hz, 1H), 4.39 (t, J =5.1 Hz, 2H), 4.23 (t, J = 5.1 Hz, 2H), 2.71 (s, 3H), 1.83 (s, 3H) 694

LCMS (ESI) m/z 594.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J =0.4 Hz, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.54 (s, 1H), 7.44-7.40 (m,2H), 7.35 (d, J = 8.9 Hz, 1H), 6.57 (d, J = 13.4 Hz, 1H), 4.37 (t, J =5.0 Hz, 4H), 4.18 (t, J = 5.0 Hz, 2H), 3.24 (s, 3H), 2.72 (s, 3H), 1.74(s, 3H) 695

LCMS (ESI) m/z 581.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H),7.69 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.43-7.39 (m, 2H), 7.35(d, J = 9.0 Hz, 1H), 4.37 (t, J = 5.0 Hz, 2H), 4.20 (d, J = 5.1 Hz, 2H),2.70 (s, 3H), 1.74 (s, 3H) 696

LCMS (ESI) m/z 608.0 ]M + 1]; +1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J =0.4 Hz, 1H), 7.65 (s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.46- 7.39(m, 2H), 7.36 (d, J = 9.0 Hz, 1H), 4.38 (s, 2H), 4.20 (s, 2H), 3.03 (s,6H), 2.72 (s, 3H), 1.81 (s, 3H) 697

LCMS (ESI) m/z 648.2 [M + 1]+; 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s,1H), 7.83 (s, 1H), 7.54 (dd, J = 8.9, 2.6 Hz, 1H), 7.52 (s, 1H), 7.33(d, J = 2.6 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 4.53- 4.28 (m, 2H),4.06-3.97 (m, 2H), 3.92-3.84 (m, 2H), 2.87 (s, 3H), 2.65 (t, J = 7.8 Hz,2H), 2.40 (q, J = 7.5 Hz, 2H), 2.04 (s, 3H) 698

LCMS (ESI) m/z 636.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H),7.55 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (s, 1H), 7.41-7.28 (m, 3H), 4.79(ddd, J = 9.4, 6.7, 1.3 Hz, 2H), 4.43 (tt, J = 6.7, 4.2 Hz, 1H),4.36-4.24 (m, 4H), 4.14 (t, J = 5.1 Hz, 2H), 2.68 (s, 3H), 1.74 (s, 3H)699

LCMS (ESI) m/z 659.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H),7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.46 (s, 1H), 7.44-7.39 (m, 2H), 7.35(d, J = 9.0 Hz, 1H), 4.89-4.75 (m, 2H), 4.50-4.45 (m, 2H), 4.36 (t, J =5.0 Hz, 2H), 4.31 (dd, J = 10.5, 4.2 Hz, 2H), 4.17 (t, J = 5.1 Hz, 2H),2.72 (s, 3H), 1.77 (s, 3H) 700

LCMS (ESI) m/z 656.9 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H),8.46 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.87 (s, 1H), 7.66-7.60 (m,2H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.47-7.40 (m, 2H), 7.36 (d, J = 9.0Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.24 (t, J = 4.9 Hz, 2H), 2.71 (s,3H), 1.80 (s, 3H) 701

LCMS (ESI) m/z 650.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H),7.55 (dd, J = 8.9, 2.7 Hz, 1H), 7.44 (s, 1H), 7.40-7.28 (m, 3H), 4.76(dd, J = 10.0, 6.5 Hz, 2H), 4.38 (dd, J = 9.8, 3.5 Hz, 2H), 4.32 (d, J =5.3 Hz, 2H), 4.22- 4.12 (m, 3H), 3.25 (s, 3H), 2.68 (s, 3H), 1.75 (s,3H) 702

LCMS (ESI) m/z 698.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H),7.59 (dd, J = 8.9, 2.6 Hz, 1H), 7.52 (s, 1H), 7.44-7.32 (m, 3H), 4.90(t, J = 9.4 Hz, 2H), 4.79 (dd, J = 10.1, 4.9 Hz, 2H), 4.43-4.31 (m, 3H),4.18 (t, J = 5.0 Hz, 2H), 3.12 (s, 3H), 2.72 (s, 3H), 1.80 (s, 3H) 703

LCMS (ESI) m/z 664.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H),7.55 (dd, J = 8.9, 2.7 Hz, 1H), 7.41 (s, 1H), 7.40-7.34 (m, 2H), 7.31(d, J = 9.0 Hz, 1H), 4.40 (d, J = 8.7 Hz, 2H), 4.32 (t, J = 5.0 Hz, 2H),4.19-4.09 (m, 4H), 3.40 (s, 2H), 2.67 (s, 3H), 1.72 (s, 3H), 1.22 (s,3H) 704

LCMS (ESI) m/z 666.4 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H),7.51 (d, J = 9.8 Hz, 2H), 7.34 (s, 1H), 7.28 (d, J = 9.1 Hz, 1H), 7.17(s, 1H), 6.66 (bs, 1H), 4.89 (t, J = 8.8 Hz, 2H), 4.39 (s, 2H),4.93-4.36 (m, 2H), 4.30 (s, 2H), 4.15 (s, 3H), 3.72 (s, 1H), 2.62 (s,3H), 2.51 (s, 2H), 2.12 (s, 3H), 1.84 (s, 4H), 1.73 (d, J = 8.4 Hz, 3H)710

MS (ESI) m/z 668.20 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.10 (bs,1H), 8.35 (s, 1H), 8.12 (s, 1H), 7.61 (dd, J = 2.56, 8.84 Hz, 1H),7.56-7.21 (m, 4H), 4.84-4.82 (m, 1H), 4.47-4.17 (m, 4H), 2.90 (s, 3H),2.71 (s, 3H), 2.66 (s, 3H), 1.78 (s, 6H) 712

MS (ESI) m/z 586.04 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.95 (bs,1H), 8.30 (s, 1H), 7.66 (s, 1H), 7.60 (dd, J = 8.84, 2.56 Hz, 1H), 7.42(s, 1H), 7.39- 7.35 (m, 2H), 4.92 (bs, 4H), 4.40 (t, J = 4.40 Hz, 2H),4.26 (t, J = 4.80 Hz, 2H), 3.13 (s, 3H), 2.71 (s, 3H), 1.93 (s, 3H) 715

MS (ESI) m/z 786.00 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H),7.70 (s, 1H), 7.54 (dd, J = 8.84, 2.48 Hz, 1H), 7.36 (d, J = 2.52 Hz,1H), 7.30 (d, J = 8.96 Hz, 1H), 7.20 (s, 1H), 5.09 (t, J = 4.6 Hz, 1H),4.89 (d, J = 3.88 Hz, 2H), 4.33 (d, J = 4.52 Hz, 2H), 4.19 (s, 2H), 2.62(s, 3H), 1.69 (s, 3H), 1.61 (s, 9H) 716

MS (ESI) m/z 784.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H),8.29 (s, 1H), 7.79 (s, 1H), 7.54 (dd, J = 8.8, 2.5 Hz, 1H), 7.36 (d, J =2.52 Hz, 1H), 7.30 (d, J = 8.92 Hz, 1H), 7.21 (s, 1H), 4.35 (t, J = 4.28Hz, 2H), 4.20 (t, J = 4.0 Hz, 2H), 2.62 (s, 3H), 1.73 (s, 3H), 1.61 (s,9H) 718

MS (ESI) m/z 657.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.54 (bs,1H), 8.30 (s, 1H), 7.58 (dd, J = 8.92 Hz, 2.6 Hz, 1H), 7.48 (s, 1H),7.39-7.34 (m, 3H), 4.38 (t, J = 5.88 Hz, 2H), 4.22 (t, J = 4.32 Hz, 2H),3.75 (s, 2H), 2.68 (s, 3H), 2.56 (s, 3H), 2.45 (bs, 4H,), 2.28 (bs, 4H),2.12 (s, 3H), 1.89 (s, 3H) 720

MS (ESI) m/z 579.93 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =4.88 Hz, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 7.59 (dd, J = 8.92, 2.68 Hz,1H), 7.50-7.44 (m, 2H), 7.40 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 8.96 Hz,1H), 4.49-4.38 (m, 5H), 4.33-4.27 (m, 2H), 1.85 (s, 3H) 724

MS (ESI) m/z 577.00 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H),7.64 (s, 1H), 7.59 (dd, J = 8.8 Hz, 2.56 Hz, 1H), 7.39-7.35 (m, 3H),5.68 (d, 46.72 Hz, 2H), 4.40 (t, 4.40 Hz, 2H), 4.25 (t, 4.56 Hz, 2H),2.69 (s, 3H), 2.53 (s, 3H), 1.95 (s, 3H) 729

MS (ESI) m/z 622.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (bs, 1H),8.71 (bs, 1H), 8.07 (d, J = 7.84 Hz, 1H), 7.93 (s, 1H), 7.62-7.56 (m,1H), 7.53- 7.49 (m, 1H), 7.30-7.28 (m, 3H), 7.12 (d, J = 7.6 Hz, 1H),4.42 (t, J = 4.76 Hz, 2H), 4.21 (t, J = 6.16 Hz, 2H), 2.72 (s, 3H), 2.66(s, 3H), 1.93 (s, 3H) 741

MS (ESI) m/z 677.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.31 (bs,1H), 7.71 (bs, 1H), 7.60 (dd, J = 2.48, 8.8 Hz 1H), 7.41 (s, 1H),7.39-7.18 (m, 2H), 4.38 (t, J = 4.12 Hz, 2H), 4.24 (t, J = 4.6 Hz, 2 H),3.81-3.21 (m, 8H), 2.93 (s, 3H), 2.71 (s, 3H), 2.50 (s, 3H), 2.02 (s,3H) 743

MS (ESI) m/z 622.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J =3.88 Hz, 1H), 8.02 (t, J = 6.20 Hz, 1H), 7.81 (d, J = 7.76 Hz, 2H),7.51-7.47 (m, 2H), 7.30-7.08 (m, 3H), 7.03 (bs, 1H), 4.32 (t, J = 6.04Hz, 2H), 4.21 (t, J = 5.4 Hz, 2H), 2.76 (s, 3H), 2.66 (s, 3H), 1.93 (s,3H) 744

MS (ESI) m/z 579.36 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.59 (bs,1H), 8.90 (s, 1H), 8.44 (s, 1H), 7.57 (d, J = 8.84 Hz, 1H), 7.41 (s,1H), 7.38 (s, 1H), 7.33 (d, J = 8.84 Hz, 1H), 4.39 (t, J = 5.4 Hz, 2H),4.21 ((t, J = 4.32 Hz, 2H)), 2.68 (s, 3H), 2.35-2.32 (m, 1H), 1.78 (s,3H), 1.29-1.07 (m, 4H) 745

MS (ESI) m/z 522.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (bs,1H), 9.04 (s, 1H), 8.47 (s, 1H), 7.59 (dd, J = 2.48, 8.88 Hz, 1H), 7.40(t, J = 2.68 Hz, 2H), 7.35 (d, J = 8.92 Hz, 1H), 4.40 (t, J = 4.32 Hz,2H), 4.23 (t, J = 5.04, 2H), 2.69 (s, 6H), 1.81 (s, 3H) 746

MS (ESI) m/z 536.27 [M + 1]+; 1H-NMR NMR (400 MHz, DMSO-d6) δ 13.58 (bs,1H), 8.49 (s, 1H), 7.59 (d, J = 8.72 Hz, 1H), 7.40-7.38 (m, 2H), 7.35(d, J = 8.84 Hz, 1H), 4.39 (bs, 2H), 4.22 (bs, 2H), 2.69 (s, 3H), 2.67(s, 3H), 2.65 (s, 3H), 1.82 (s, 3H) 748

MS (ESI) m/z 571.01 [M + 1]+. 1H-NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H),7.59 (dd, J = 8.80, 2.80 Hz 1H), 7.44- 7.40 (m, 2H), 7.40-7.34 (m, 2H),4.39 (t, J = 4.96 Hz, 2H), 4.24 (t, J = 4.52 Hz, 2H), 3.10 (t, J = 7.12Hz, 4H), 2.71 (s, 3H), 2.21-2.14 (m, 2H), 1.96 (s, 3H) 750

MS (ESI) m/z 695.96 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H),7.62 (s, 1H), 7.69-7.56 (m, 1H), 7.42 (d, J = 2.44 Hz, 1H), 7.39 (s,1H), 7.34 (d, J = 8.84 Hz, 1H), 4.35 (t, J = 4.84 Hz, 2H), 4.26 (t, J =7.52 Hz, 4H), 4.16 (t, J = 4.36 Hz, 2H), 2.70 (s, 3H), 2.31-2.27 (m,2H), 1.73 (s, 3H) 752

MS (ESI) m/z 620.00 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H),7.58 (dd, J = 2.56, 8.80 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J = 2.56 Hz,1H), 7.38 (s, 1H), 7.34 (d, J = 9.04 Hz, 1H), 4.60 (t, J = 7.60 Hz, 4H),4.35 (t, J = 5.12 Hz, 2H), 4.16 (t, J = 4.12 Hz, 2H), 2.70 (s, 3H),2.32- 2.26 (m, 2H), 1.77 (s, 3H) 755

MS (ESI) m/z 1136.89 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J =4.8 Hz, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.72 (bs, 1H),7.61-7.58 (m, 1H), 7.54-7.35 (m, 5H), 6.40 (s, 1H), 6.35 (s, 1H),4.46-4.12 (m, 11H), 3.47-3.33 (m, 13H), 3.04-3.01 (m, 4H), 2.66-2.50 (m,4H), 2.03-2.00 (m, 4H), 1.81 (s, 3H), 1.58-1.55 (m, 4H), 1.47-1.43 (m,4H), 1.25-1.20 (m, 2H) 758

MS (ESI) m/z 692.00 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.56 (bs,1H), 8.47 (s, 1H), 8.28 (t, J = 7.84 Hz, 1H), 7.94 (d, J = 7.72 Hz, 1H),7.91-7.86 (m, 2H), 7.59 (dd, J = 8.88, 2.56 Hz, 1H), 7.44-7.39 (m, 2H),7.35 (d, J = 8.96 Hz, 1H), 7.04 (t, J = 54.68 Hz, 1H), 4.39 (t, J = 4.64Hz, 2H), 4.25 (t, J = 5.44 Hz, 2H), 2.71 (s, 3H), 1.86 (s, 3H) 761

MS (ESI) m/z 651.05 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H),8.80 (d, J = 5.8 Hz, 2H), 8.57 (s, 1H), 7.63 (d J = 5.56 Hz, 2H), 7.59(dd, J = 8.92 Hz, 2.56, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.40 (s, 1H),7.36 (d, J = 8.96, 1H), 4.42 (t, J = 5.4 Hz, 2H), 4.32 (t, J = 4.24 Hz,2H), 2.71 (s, 3H), 2.00 (s, 3H) 759

MS (ESI) m/z 622.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.63 (bs,1H), 8.77 (s, 1H), 8.71 (s, 1H), 8.35 (s, 1H), 8.03 (d, J = 6.96 Hz,1H), 7.61-7.59 (m, 2H), 7.52 (s, 1H), 7.43-7.36 (m, 3H), 4.42 (t, J =5.76 Hz, 2H), 4.26 (t, J = 5.48 Hz, 2H), 2.71 (s, 3H), 2.5 (s, 3H, notvisible, merged with moisture peak), 1.87 (s, 3H) 760

MS (ESI) m/z 589.98 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H),7.59 (dd, J = 8.88, 2.6 Hz, 1H), 7.42 (d J = 2.56 Hz, 1H), 7.39 (s, 1H),7.35 (d, J = 8.96 Hz, 1H), 4.40 (t, J = 4.72 Hz, 2H), 4.28 (t, J = 4.8Hz, 2H), 2.79 (s, 3H), 2.69 (s, 3H), 1.98 (s, 3H) 766

MS (ESI) m/z 630.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H),7.89 (s, 1H), 7.59 (dd, J = 90.20, 2.52 Hz, 1H), 7.42 (s, 2H), 7.34 (d,J = 8.96 Hz, 1H), 4.36 (t, J = 5.64 Hz, 2H), 4.22- 4.18 (m, 6H), 2.70(s, 3H), 2.36-2.30 (m, 2H), 1.72 (s, 3H) 764

MS (ESI) m/z 652.95 [M + 1]+, 1H NMR (400 MHz, DMSO-d6) δ 13.57 (bs,1H), 9.09 (s, 1H), 8.84 (d, J = 2.44 Hz, 1H), 8.80 (bs, 1H), 8.37 (s,1H), 8.35 (s, 1H), 7.58 (dd, J = 2.56, 8.88 Hz, 1H), 7.43 (bs, 2H), 7.35(d, J = 8.96 Hz, 1H), 4.41 (t, J = 4.96 Hz, 2H), 4.28 (t, J = 4.36 Hz,2H), 2.70 (s, 3H), 1.83 (s, 3H) 765

MS (ESI) m/z 652.95 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.61 (bs,1H), 9.02 (d, J = 4.92 Hz, 2H), 8.40 (s, 1H), 8.34 (s, 1H), 7.70 (t, J =4.92 Hz, 1H), 7.58 (dd, J = 8.92, 2.52 Hz, 1H), 7.43 (d, J = 2.48 Hz,1H), 7.41 (s, 1H), 7.34 (d, J = 8.96 Hz, 1H), 4.39-4.37 (m, 2H),4.30-4.23 (m, 2H), 2.69 (s, 3H), 1.80 (s, 3H) 769

MS (ESI) m/z 667.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (bs,1H), 8.95 (d, J = 5.12 Hz, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 7.75 (d, J =5.08 Hz, 1H), 7.59 (dd, J = 2.52, 8.84 Hz, 1H), 7.42 (t, J = 2.64 Hz,2H), 7.35 (d, J = 8.96 Hz, 1H), 4.40 (t, J = 6.64 Hz, 2H), 4.27 (t, J =6.6 Hz, 2H), 2.71 (s, 6H), 1.81 (s, 3H) 767

MS (ESI) m/z 652.92 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (bs, 1H)9.35 (d, J = 0.88 Hz, 1H), 9.08 (d, J = 5.16 Hz, 1H), 8.37 (s, 1H), 8.35(s, 1H), 7.98 (dd, J = 4.04, 1.52 Hz, 1H), 7.59 (dd, J = 9.20, 2.40, Hz,1H), 7.43-7.41 (m, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.40 (t, J = 3.76 Hz,2H), 4.27 (t, J = 4.48 Hz, 2H), 2.70 (s, 3H), 1.83 (s, 3H) 768

MS (ESI) m/z 653.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (bs,1H), 9.38 (s, 1H), 9.03 (s, 2H), 8.31 (d, J = 2.88 Hz, 1H), 7.59 (dd, J= 8.80, 2.40 Hz, 1H), 7.43-7.41 (m, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.41(t, J = 4.80 Hz, 2H), 4.27 (t, J = 4.80 Hz, 2H), 2.72 (s, 3H), 1.85 (s,3H) 781

MS (ESI) m/z 646.02 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H),8.27 (s, 1H), 7.62-7.57 (dd, J = 2.6, 8.8 Hz, 1H), 7.44-7.43 (m, 2H),7.36 (d, J = 9.2 Hz, 1H), 4.39 (t, J = 4.4 Hz, 2H), 4.25 (t, J = 4.4 Hz,2H), 3.06 (s, 3H), 2.79 (s, 3H), 2.71 (s, 3H), 1.78 (s, 3H) 778

MS (ESI) m/z 639.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =5.28 Hz, 1H), 8.43 (s, 1H), 7.76 (s, 1H), 7.70 (d, J = 4.88, 1H),7.61-7.58 (m, 2H), 7.43 (s, 1H), 7.41 (d, J = 2.48 Hz, 1H), 7.37 (d, J =8.96 Hz, 1H), 4.41 (t, J = 5.32 Hz, 2H), 4.27 (t, J = 4.28 Hz, 2H), 2.73(s, 3H), 2.67 (s, 3H), 1.94 (s, 3H) 780

MS (ESI) m/z 616.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H),8.32 (s, 1H), 8.25 (s, 1H), 7.60 (dd, J = 2.56, 8.84 Hz 1H), 7.42-7.41(m, 2H), 7.36 (d, J = 8.96 Hz, 1H), 4.41 (t, J = 4.56 Hz, 2H), 4.28 (t,J = 4.28 Hz, 2H), 2.72 (s, 3H), 2.71 (s, 3H), 1.81 (s, 3H) 784

MS (ESI) m/z 612.97 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),8.08 (s ,1H), 7.59 (dd, J = 2.48, 8.88 Hz, 1H), 7.41 (d, J = 2.6 Hz,2H), 7.35 (d, J = 8.96 Hz, 1H), 4.37 (t, J = 4.48 Hz, 2H), 4.23 (t, J =4.92 Hz, 2H), 2.69 (s, 3H), 2.19 (s, 3H), 1.76 (s, 3H) 782

MS (ESI) m/z 653.03 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 13.5 (bs, 1H),8.40 (s, 1H), 8.32 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.41 (s, 2H), 7.33(d, J = 9.0 Hz, 1H), 4.40 (bs, 2H), 4.27 (bs, 2H), 3.54 (s, 3H), 2.70(s, 3H), 1.78 (s, 3H) 783

MS (ESI) m/z 598.95 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (bs,1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.60-7.57 (dd, J = 8.84, 2.4 Hz, 2H),7.41 (d, J = 3.48 Hz 1H), 7.34 (d, J = 8.92 Hz, 1H), 4.89 (s, 1H), 4.38(t, J = 3.84 Hz, 2H), 4.24 (t, J = 4.52 Hz, 2H), 2.69 (s, 3H), 1.76 (s,3H) 787

MS (ESI) m/z 654.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.60 (bs,1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.82 (d, J = 1.96 Hz, 1H), 7.58 (dd, J= 8.88, 2.48 Hz, 1H), 7.42 (d, J = 2.52 Hz, 1H), 7.40 (s, 1H), 7.34 (d,J = 8.96 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 4.39 (t, J = 4.40 Hz, 2H),4.25 (t, J = 4.00 Hz, 2H), 3.94 (s, 3H), 2.68 (s, 3H), 1.77 (s, 3H) 785

MS (ESI) m/z 600.0 [M + 1]+. 1H-NMR (400 MHz, DMSO-d6) ) δ 8.33 (s, 1H),8.24 (s ,1H), 7.60 (dd, J = 2.52, 8.84 Hz, 1H), 7.43 (s, 1H), 7.41 (d, J= 2.52 Hz, 1H), 7.35 (d, J = 8.96 Hz, 1H), 4.40 (t, J = 4.4 Hz, 2H),4.27 (t, J = 6.0 Hz, 2H), 2.70 (s, 3H), 1.75 (s, 3H) 786

MS (ESI) m/z 615.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H),8.00 (s, 1H), 7.59 (d, J = 7.72 Hz, 1H), 7.42 (d, J = 1.92 Hz, 1H), 7.40(s, 1H), 7.34 (d, J = 9.04 Hz, 1H), 4.37 (t, J = 4.12 Hz, 2H), 4.19 (t,J = 5.04 Hz, 2H), 3.01 (s, 6H), 2.69 (s, 1H), 1.72 (s, 3H) 795

MS (ESI) m/z 615.04 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (bs,1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.59 (dd, J = 2.40, 8.76 Hz, 1H), 7.42(d, J = 2.52 Hz, 1H), 7.39 (s, 1H), 7.33 (d, J = 8.96 Hz, 1H), 4.37 (bs,2H), 4.21 (bs, 2H), 2.68 (s, 3H), 2.37-2.32 (m, 1H), 1.76 (s, 3H), 1.19-1.13 (m, 4H) 788Fa

MS (ESI) m/z 676.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H),8.43 (d, J = 5.0 Hz, 1H), 8.21 (d, J = 6.6 Hz, 2H), 8.11 (d, J = 7.56Hz, 1H), 7.62 (s, 1H), 7.60-7.56 (m, 1H), 7.43 (d, J = 2.6 Hz, 2H), 7.35(d, J = 8.8 Hz, 2H), 4.40 (t, J = 6.7 Hz, 2H), 4.24 (t, J = 5.0 Hz, 2H),2.58 (s, 3H), 1.71 (s, 3H) 788Fb

MS (ESI) m/z 694.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H),8.63 (d, J = 4.9 Hz, 1H), 8.40 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.61(d, J = 7.4 Hz, 1H), 7.52 (dd, J = 2.4, 4.9 Hz, 1H), 7.45 (s, 1H), 7.37(s, 2H), 7.31-7.29 (m, 1H), 7.26 (s, 2H), 4.35 (bs, 2H), 4.24 (bs, 2H),2.58 (s, 3H), 1.75 (s, 3H) 798

MS (ESI) m/z 725.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H),7.66 (s, 1H), 7.58 (dd, J = 8.88, 2.56 Hz 1H), 7.43-7.38 (m, 2H), 7.35(d, J = 8.96 Hz, 1H), 4.37 (t, J = 6.00 Hz, 2H), 4.20 (t, J = 4.28 Hz,2H), 3.55-3.44 (m, 4H), 2.70 (s, 3H), 2.05-1.94 (m, 4H), 1.81 (s, 3H)796

MS (ESI) m/z 644.27 [M + 1]+; 1H-NMR (400 MHz, DMSO-d6) δ 13.60 (bs,1H), 8.34 (s, 1H), 8.02 (s ,1H), 7.59 (dd, J = 2.52, 8.88 Hz, 1H), 7.41(d, J = 2.52 Hz, 1H),7.39 (s, 1H), 7.35 (d, J = 8.96 Hz, 1H), 5.03 (s,4H), 4.37 (t, J = 5.28 Hz, 2H), 4.23 (t, J = 6.32 Hz, 2H), 2.70 (s, 3H),1.75 (s, 3H) 797

MS (ESI) m/z 644.0 [M − 1]−; 1H-NMR (400 MHz, DMSO-d6) ) δ 13.59 (bs,1H), 8.39 (s, 1H), 7.90 (s ,1H), 7.59 (dd, J = 2.44, 8.88 Hz, 1H), 7.41(d, J = 2.48 Hz, 1H), 7.38 (s, 1H), 7.33 (d, J = 8.96 Hz, 1H), 5.70 (d,J = 5.84 Hz, 1H), 4.57-4.56 (m, 1H), 4.38-4.32 (m, 4H), 4.18 (d, J = 4.2Hz, 2H), 3.96-3.92 (m, 2H), 2.68 (s, 3H), 1.71 (s, 3H) 801

MS (ESI) m/z 686.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (bs,1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.59 (dd, J = 2.60, 8.92 Hz, 1H), 7.42(d, J = 2.56 Hz, 1H), 7.39 (s, 1H), 7.33 (d, J = 8.96 Hz, 1H), 4.37 (t,J = 4.64 Hz, 2H), 4.20 (t, J = 5.56 Hz, 2H), 3.23 (t, J = 5.16 Hz, 4H),2.68 (s, 3H), 1.78 (s, 3H), 1.48 (t, J = 5.2 Hz, 4H), 0.99 (s, 6H) 799

MS (ESI) m/z 671.94 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.55 (bs,1H), 8.42 (s, 1H), 7.69 (s, 1H), 7.58 (dd, J = 2.36, 8.84 Hz, 1H), 7.40(d, J = 2.52 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J = 9.00 Hz, 1H), 7.33 (t,J = 54.04 Hz, 1H), 4.92 (t, J = 12.44 Hz, 4H), 4.38 (t, J = 5.36 Hz,2H), 4.20 (t, J = 5.80 Hz, 2H), 2.70 (s, 3H), 1.82 (s, 3H) 800

MS (ESI) m/z 672.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H),8.03 (s, 1H), 7.59 (dd, J = 2.56, 8.88 Hz, 1H), 7.42 (d, J = 2.56 Hz,1H), 7.39 (s, 1H), 7.33 (d, J = 8.96 Hz, 1H), 4.37 (t, J = 5.48 Hz, 2H),4.20 (t, J = 4.32 Hz, 2H), 3.55 (d, J = 12.44 Hz, 2H), 2.90 (t, J =11.90 Hz, 2H), 2.68 (s, 3H), 1.74-1.72 (m, 5H), 1.58 (bs, 1H), 1.31-1.23(m, 2H), 0.97 (d, J = 6.44 Hz, 3H) 804

MS (ESI) m/z 681.96 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H),8.59 (d, J = 3.56, 1H), 8.35 (s, 1H), 8.14 (s, 1H) 7.87 (t, J = 6.92 Hz,1H), 7.59- 7.53 (m, 2H), 7.42-7.40 (m, 2H), 7.38- 7.33 (m, 2H), 5.66 (s,2H), 4.39 (t, J = 4.36 Hz, 2H), 4.22 (t, J = 4.04 Hz, 2H), 2.70 (s, 3H),1.75 (s, 3H) 802

MS (ESI) m/z 694.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (bs,1H), 8.33 (s, 1H), 8.10 (s, 1H), 7.58 (d, J = 7.08, 1H), 7.41-7.32 (m,3H), 4.38 (t, J = 3.64 Hz, 2H), 4.21 (t, J = 5.68 Hz, 2H), 3.35 (t, J =5.08 Hz, 4H), 2.68 (s, 3H), 2.14 (t, J = 13.4 Hz, 4H), 1.76 (s, 3H) 803

MS (ESI) m/z 725.97 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H),8.06 (s, 1H), 7.58 (d, J = 8.60 Hz, 1H), 7.41 (s, 2H), 7.34 (d, J = 8.96Hz, 1H), 4.38 (t, J = 5.16 Hz, 2H), 4.21 (t, J = 5.52 Hz, 2H), 3.62 (d,J = 12.52 Hz, 2H), 2.97 (t, J = 12.12 Hz, 2H), 2.70 (s, 3H), 1.94 (d, J= 11.96 Hz, 2H), 1.76 (s, 3H), 1.64-159 (m, 2H) 810

MS (ESI) m/z 605.8 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J =0.8 Hz, 1H), 8.44 (s, 1H), 7.58 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (d, J =2.7 Hz, 1H), 7.36 (s, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.11 (d, J = 0.9Hz, 1H), 4.48 (d, J = 12.6 Hz, 2H), 4.36 (t, J = 5.1 Hz, 2H), 4.21 (t, J= 5.1 Hz, 2H), 3.56 (bd, J = 11.0 Hz, 2H), 3.25-3.04 (m, 4H), 2.88 (d, J= 3.5 Hz, 3H), 2.69 (s, 3H), 1.83 (s, 3H) 805

MS (ESI) m/z 614.99 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H),7.59 (dd, J = 8.80, 2.40 Hz, 1H), 7.43- 7.41 (m, 3H), 7.36 (d, J = 8.80Hz, 1H), 6.19 (s, 1H), 4.38 (t, J = 4.92 Hz, 2H), 4.22 (t, J = 6.00 Hz,2H), 2.78-2.50 (m, 5H), 2.09-2.01 (m, 4H), 1.86 (s, 3H) 806

MS (ESI) m/z 583.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.89 (bs,1H), 8.07 (bs, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.52-7.12(m, 6H), 4.35 (s, 4H), 4.13 (s, 2H), 2.56 (bs, 6H), 2.14 (s, 3H) 841

MS (ESI) m/z = 580.3 [M + 1]+; 1H-NMR (400 MHz, d6-DMSO) δ/ppm = 9.74-9.62 (b, 1H), 8.84 (d, J = 4.7 Hz, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.38(s, 1H), 7.59 (dd, J = 8.9, 2.7 Hz, 1H), 7.46-7.43 (m, 2H), 7.32 (d, J =8.9 Hz, 1H), 4.54 (t, J = 4.4 Hz, 2H), 4.34 (t, J = 4.9 Hz, 2H), 4.18(t, J = 4.9 Hz, 2H), 3.61-3.56 (m, 2H), 2.98 (d, J = 4.4 Hz, 6H), 1.80(s, 3H) 811

MS (ESI) m/z 604.8 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H),7.57 (td, J = 8.9, 2.8 Hz, 2H), 7.42 (d, J = 2.7 Hz, 1H), 7.39-7.27 (m,4H), 4.36 (t, J = 5.1 Hz, 2H), 4.22 (t, J = 5.0 Hz, 2H), 3.97 (d, J =13.2 Hz, 2H), 3.57 (d, J = 12.3 Hz, 2H) 3.29-3.13 (m, 2H), 3.04 (t, J =12.6 Hz, 2H), 2.89 (d, J = 4.0 Hz, 3H), 2.68 (s, 3H), 1.82 (s, 3H). 812

MS (ESI) m/z 643.6 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J =9.0 Hz, 1H), 7.64- 7.57 (m, 2H), 7.43-7.34 (m, 3H), 4.41 (t, J = 5.0 Hz,2H), 4.24 (t, J = 5.1 Hz, 2H), 3.82-3.55 (m, 4H), 3.25 (bd, J = 9.1 Hz,4H), 2.92 (s, 3H), 2.70 (s, 3H), 2.48 (s, 3H), 1.95 (s, 3H) 877

LCMS (ESI) m/z 671.1 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H),8.18 (d, J = 8.8 Hz, 1H), 8.07 (s, 1H), 7.63 (s, 1H), 7.56 (dd, J = 8.9,2.7 Hz, 1H), 7.41-7.28 (m, 2H), 4.37 (t, J = 5.0 Hz, 1H), 4.22 (d, J =5.0 Hz, 1H), 3.38 (d, J = 12.0 Hz, 1H), 3.09 (d, J = 12.0 Hz, 1H), 2.67(s, 2H), 2.17 (s, 2H), 1.94 (t, J = 11.8 Hz, 1H), 1.81 (s, 3H) 849

LCMS: 672.9 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.48 (s,1H), 8.41 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.43 (d, J = 2.7 Hz,1H), 7.40- 7.31 (m, 2H), 4.41 (t, J = 5.1 Hz, 2H), 4.27 (t, J = 5.2 Hz,2H), 3.37-3.12 (m, 6H), 2.93 (d, J = 2.7 Hz, 3H), 2.69 (s, 3H), 1.99 (s,3H) 858

LCMS: 631.4 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.77-9.57 (m, 1H),8.79 (d, J = 4.8 Hz, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H), 7.56(dd, J = 8.9, 2.7 Hz, 1H), 7.41 (dd, J = 12.9, 3.7 Hz, 2H), 7.32 (d, J =9.0 Hz, 1H), 4.36 (t, J = 5.1 Hz, 2H), 4.22 (t, J = 5.0 Hz, 2H), 3.34(t, J = 6.2 Hz, 2H), 3.20 (dd, J = 11.3, 5.4 Hz, 2H), 2.88 (d, J = 4.3Hz, 6H), 1.78 (s, 3H) 896

MS (ESI) m/z 668.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H),7.74 (bs, 1H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H), 7.49-7.13 (m, 4H), 4.39(bs, 2H), 4.23 (bs, 2H), 3.58 (bs, 2H), 3.03-2.98 (m, 2H), 2.25 (bs,6H), 1.78 (s, 3H), 1.37 (t, J = 7.6 Hz, 3H) 880

LCMS (ESI) m/z 643.1 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J =4.8 Hz, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.06 (s, 1H), 7.70 (s, 1H),7.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.45-7.37 (m, 2H), 7.32 (d, J = 9.0 Hz,1H), 4.36 (t, J = 5.0 Hz, 2H), 4.21 (t, J = 5.1 Hz, 2H), 3.19 (s, 1H),3.09 (d, J = 11.9 Hz, 2H), 1.94 (q, J = 13.5, 12.6 Hz, 4H), 1.79 (s, 3H)881

LCMS (ESI) m/z 657.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J =4.8 Hz, 1H), 8.24 (s, 1H), 8.02 (s, 1H), 7.70 (s, 1H), 7.56 (dd, J =8.9, 2.7 Hz, 1H), 7.45-7.37 (m, 2H), 7.32 (d, J = 9.0 Hz, 1H), 4.36 (t,J = 5.0 Hz, 2H), 4.21 (t, J = 5.0 Hz, 2H), 3.21-3.11 (m, 3H), 2.82 (d, J= 4.6 Hz, 3H), 1.99 (s, 3H), 1.78 (s, 3H) 920

MS (ESI) m/z 662.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H),7.74 (d, J = 8.72 Hz, 1H), 7.57 (dd, J = 2.12, 8.76 Hz, 1H), 7.41 (d, J= 2.08 Hz, 1H), 7.39 (bs, 1H), 7.34(d, J = 8.92 Hz, 1H), 4.37 (bs, 2H),4.19 (bs, 2H), 3.60- 3.57 (m, 1H), 3.47-3.41 (m, 1H), 2.69 (s, 3H),2.10-2.05 (m, 2H), 1.89-1.86 (m, 2H), 1.79 (s, 3H), 1.25 (s, 3H), 1.12(s, 3H) 918

MS (ESI) m/z 648.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (bs,1H), 8.37 (s, 1H), 7.62-7.57 (m, 2H), 7.42- 7.33 (m, 3H), 4.41-4.37 (m,4H), 4.18 (s, 2H), 2.69 (s, 3H), 2.25 (t, J = 7.52 Hz, 2H), 1.74 (s,3H), 1.53 (s, 6H). 919

MS (ESI) m/z 684.04 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H),7.68 (s, 1H), 7.59 (dd, J = 2.48, 8.84 Hz, 1H), 7.40 (bs, 2H), 7.35 (d,J = 8.92 Hz, 1H), 4.38 (t, J = 5.92 Hz, 2H), 4.22 (t, J = 6.52 Hz, 2H),3.45 (t, J = 5.96 Hz, 4H), 2.71 (s, 3H), 2.21-2.16 (m, 4H), 1.86 (s, 3H)933

MS (ESI) m/z 668.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H),7.79 (s, 1H), 7.60 (dd, J = 8.84, 2.6 Hz, 1H), 7.51 (bs, 2H), 7.42 (s,1H), 7.40 (d, J = 2.56 Hz, 1H), 7.37 (d, J = 9 Hz, 1H), 5.32 (d, J =46.4 Hz, 2H), 4.41 (t, J = 3.04 Hz, 2H), 4.27 (t, J = 5.12 Hz, 2H), 2.72(s, 3H), 2.64 (s, 6H), 1.96 (s, 3H) 921

MS (ESI) m/z 646.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H),8.02 (s, 1H), 7.59 (dd, J = 2.56 Hz, J = 8.88 Hz, 1H), 7.55 (d, J =10.16 Hz, 1H), 7.43 (s, 1H), 7.41 (d, J = 2.56 Hz, 1H), 7.36 (d, J =8.96 Hz, 1H), 4.40 (t, J = 5.88 Hz, 2H), 4.25 (t, J = 4.44 Hz, 2H), 2.79(s, 3H), 2.72 (s, 3H), 1.90 (s, 3H) 932

MS (ESI) m/z 654.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H),7.69-7.55 (m, 4H), 7.43 (s, 1H), 7.40 (d, J = 2.52 Hz, 1H), 7.32 (d, J =8.96 Hz, 1H), 4.44-4.38 (m, 2H) 4.26 (t, J = 5.40 Hz, 2H), 2.73 (s, 3H),2.65 (s, 6H), 1.93 (s, 3H) 938

MS (ESI) m/z 633.05 [M + 1]+.1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H),8.38 (s, 1H), 8.14 (s, 1H), 7.57 (bs, 1H), 7.42-7.33 (m, 3H), 5.36 (bs,1H), 4.39 (bs, 2H), 4.23 (bs, 2H), 2.67 (s, 3H), 1.79 (s, 3H), 1.58 (s,6H) 935

MS (ESI) m/z 625.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.59 (bs,1H), 8.46 (s, 1H), 7.58-7.51 (m, 7H), 7.42 (s, 2H), 7.37 (d, J = 8.44Hz, 1H), 4.40 (t, J = 3.72, 2H), 4.25 (t, J = 5.12, 2H), 2.72 (s, 3H),1.85 (s, 3H). 936

MS (ESI) m/z 646.04 [M + 1]+, 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H),8.45 (s, 1H), 7.61-7.57 (m, 2H), 7.43 (bs, 2H), 7.33 (t, J = 19.2Hz,1H), 4.40 (t, J = 5.68 Hz, 2H), 4.25 (d, J = 4.48 Hz, 2H), 2.72 (s, 3H),2.30 (s, 3H), 1.85 (s, 3H). 956

MS (ESI) m/z 636.11 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.47 (s, 1H),8.38 (s, 1H), 7.73 (s, 1H), 7.58 (dd, J = 2.32 Hz, J = 8.80 Hz, 1H),7.43 (d, J = 2.28 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J = 8.96 Hz, 1H), 4.55(s, 1H), 4.37 (t, J = 5.12 Hz, 2H), 4.19 (t, J = 6.04 Hz, 2H), 2.69 (s,3H), 1.74 (s, 3H), 1.32 (s, 9H) 939

MS (ESI) m/z 671.98 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.61 (bs,1H), 9.19 (s, 1H), 8.35 (s, 1H), 7.58 (dd, J = 8.88, 2.56 Hz, 1H), 7.44(s, 2H), 7.35 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 5.0 Hz, 2H), 4.26 (t, J= 5.44, 2H), 2.72 (s, 3H), 2.20 (s, 3H), 1.81 (s, 3H) 955

MS (ESI) m/z 650.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H),8.34 (s, 1H), 7.72 (s, 1H), 7.58 (dd, J = 1.48 Hz, J = 7.80 Hz, 1H),7.42 (d, J = 1.76 Hz, 1H), 7.40 (s, 1H), 7.50 (d, J = 8.88, 1H), 4.38(t, J = 5.80, 2H), 4.20 (t, J = 4.32, 2H), 2.90 (s, 3H), 2.70 (s, 3H),1.77 (s, 3H), 1.25 (s, 9H) 959

MS (ESI) m/z 685.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H),8.41 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.62-7.59 (m, 3H), 7.44 (s,2H), 7.37 (d, J = 8.96 Hz, 1H), 4.40 (t, J = 2.76 Hz, 2H), 4.26 (t, J =3.72 Hz, 2H), 3.44 (s, 3H), 2.73 (s, 3H), 2.57 (s, 3H), 1.85 (s, 3H) 957

MS (ESI) m/z 634.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.4 (s, 1H),8.39 (s, 1H), 7.69 (s, 1H), 7.59 (dd, J = 8.84, 2.44 Hz, 1H), 7.42 (d, J= 2.4 Hz, 1H), 7.38 (s, 1H), 7.35 (d, J = 8.92 Hz, 1H), 4.37 (bs, 2H),4.19 (bs, 2H), 3.08 (t, J = 10.36 Hz, 1H), 3.02 (s, 3H), 2.69 (s, 3H),1.78 (s, 3H), 0.63 (d, J = 4.92 Hz, 2H), 0.37 (bs, 2H) 958

MS (ESI) m/z 620.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H),7.59 (d, J = 2.2 Hz, 1H), 7.54 (s, 1H), 7.43 (d, J = 2.4 Hz, 2H), 7.36(d, J = 8.92 Hz, 1H), 6.66 (s, 1H), 4.36 (bs, 2H), 4.10 (bs, 2H), 3.16(d, J = 6.84 Hz, 1H), 2.70 (s, 3H), 1.80 (s, 3H), 0.867-0.82 (m, 2H),0.65-0.62 (m, 2H) 962

MS (ESI) m/z 675.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H),8.45 (s, 1H), 8.09 (s, 1H), 8.03 (d, J = 2.04, 1H), 7.85 (s, 1H), 7.59(dd, J = 8.84 Hz, 2.36 Hz, 1H), 7.44 (s, 2H), 7.36 (d, J = 8.92 Hz, 1H),7.04 (d, J = 11.12 Hz, 1H), 4.39 (t, J = 4.64 Hz, 2H), 4.22 (t, J = 4.48Hz, 2H), 2.72 (s, 3H), 1.75 (s, 3H) 960

MS (ESI) m/z 671.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H),8.45 (s, 1H), 8.20 (d, J = 2.20, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.60(dd, J = 2.32 Hz, J = 8.72 Hz, 2H), 7.43- 7.42 (m, 2H), 7.36 (d, J =8.92 Hz, 1H), 4.39 (t, J = 5.56 Hz, 2H), 4.24 (t, J = 3.56 Hz, 2H), 2.71(s, 3H), 2.55 (s, 3H), 1.81 (s, 3H) 961

MS (ESI) m/z 689.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H),8.01 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.59 (d, J = 8.80 Hz, 1H),7.44 (s, 2H), 7.36 (d, J = 8.80 Hz, 1H), 7.04 (d, J = 12.04 Hz, 1H),4.39 (s, 2H), 4.25 (s, 2H), 3.39 (s, 3H), 2.73 (s, 3H), 1.80 (s, 3H)1001

MS (ESI) m/z [M + 1]+, 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.64(s, 1H), 8.38 (s, 1H), 8.02 (d, J = 6.96 Hz,1H), 7.59 (d, J = 6.76 Hz,1H), 7.39-7.35 (m, 3H), 6.18 (s, 1H), 4.37 (s, 2H), 4.22 (s, 2H), 2.68(s, 3H), 2.30 (s, 3H), 1.78 (s, 3H), 1.05 (t, J = 7.16 Hz, 1H). 990

MS (ESI) m/z 721.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.63 (bs,1H), 9.18 (s, 1H), 9.13 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.58 (dd, J= 2.52, 8.88 Hz, 1H), 7.44-7.43 (m, 2H), 7.34 (d, J = 8.96 Hz, 1H), 4.39(t, J = 5.00 Hz, 2H), 4.26 (t, J = 4.36 Hz, 2H), 2.70 (s, 3H), 1.82 (s,3H) 1000

MS (ESI) m/z [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.49(s, 1H), 7.86 (t, J = 9.12 Hz, 1H), 7.74-7.66 (m, 2H), 7.54-7.38 (m,3H),6.21 (s, 1H), 4.40 (t, J = 4.48, 2H), 4.24 (t, J = 4.64, 2H), 2.69(s, 3H), 2.54 (s, 3H), 1.69 (s, 3H). 1005

MS (ESI) m/z 562.18 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.64 (bs,1H), 8.58 (s, 1H), 8.56 (s, 1H), 7.62-7.56 (m, 1H), 7.43-.7.39 (m, 2H),7.34 (d, J = 8.92 Hz, 1H), 4.35 (t, J = 4.68 Hz, 2H), 4.41 (t, J = 4.48Hz, 2H), 3.70 (s, 3H), 2.72 (s, 3H), 1.71 (s, 3H) 1002

MS (ESI) m/z 574 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.52 (bs, 1H),8.57 (s, 1H), 8.49 (s, 1H), 7.57 (d, J = 8.52 Hz, 1H), 7.39-7.33 (m,3H), 5.91 (s, 1H), 4.37 (t, J = 5.08 Hz, 2H), 4.16 (t, J = 4.04 Hz, 2H),3.21 (s, 6H), 2.70 (s, 3H), 1.63 (s, 3H) 1003

MS (ESI) m/z 586.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.49 (bs,1H), 8.56 (s, 1H), 8.48 (s, 1H), 7.56 (d, J = 8.84 Hz, 1H), 7.39 (s,1H), 7.40-7.33 (m, 2 H), 5.89 (s, 1H), 4.37-4.32 (m, 6H), 4.15 (t, J =5.36 Hz, 2H), 2.69 (s, 3H), 1.69 (s, 3H), 2.38-2.32 (m, 2H) 1018

MS (ESI) m/z 667.06 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (bs,1H), 8.95 (s, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 8.32 (s, 1H), 7.58 (dd, J= 8.92, 2.40 Hz, 1H), 7.42 (s, 2H), 7.35 (d, J = 8.92 Hz, 1H), 4.40 (s,2H), 4.27 (s, 2H), 2.70 (s, 3H), 2.62 (s, 3H), 1.81 (s, 3H) 1006

MS (ESI) m/z 632.03 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H),8.48 (s, 1H), 7.91 (s, 1H), 7.63-7.56 (m, 2H), 7.46-7.40 (m, 2H), 7.35(d, J = 8.96 Hz, 1H), 4.39 (t, J = 5.96 Hz, 2H), 4.24 (t, J = 5.44 Hz,2H), 2.71 (s, 3H), 1.81 (s, 3H) 1007

MS (ESI) m/z 591.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (bs,1H), 8.69 (s, 1H), 8.46 (s, 1H), 7.59 (dd, J = 2.52, 8.64 Hz, 1H),7.43-7.42 (m, 3H), 7.34 (s, 1H), 7.32 (s, 1H), 4.34 (t, J = 5.04 Hz,2H), 4.15(t, J = 4.68 Hz, 2H), 2.70 (s, 3H), 1.69 (s, 3H) 1021

MS (ESI) m/z 721.05 [M − 1]−; 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H),9.41 (s, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 7.59 (dd, J = 2.0, 8.8 Hz,1H), 7.42 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H, 4.41 (bs, 2H), 4.29 (bs,2H), 2.69 (s, 3H), 1.83 (s, 3H) 1019

MS (ESI) m/z 667.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) 13.60 (s,1H),8.72 (d, J = 2.36 Hz, 1H), 8.61 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H),7.58 (dd, J = 8.76, 2.36 Hz, 1H), 7.47-7.40 (m, 2H), 7.35 (d, J = 8.96Hz, 1H), 4.40 (t, J = 4.3 Hz, 2H), 4.26 (t, J = 4.8 Hz, 2H), 2.71 (s,3H), 2.35 (s, 3H), 1.82 (s, 3H) 1020

MS (ESI) m/z 703.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.56 (bs,1H), 9.24 (s, 1H), 9.12 (s, 1H), 8.37 (d, J = 7.00 Hz, 2H), 7.60 (dd, J= 2.44, 8.88 Hz, 1H), 7.42-7.13 (m, 4H), 4.42 (t, J = 5.68 Hz, 2H), 4.28(t, J = 5.16 Hz, 2H), 2.71 (s, 3H) 1.84 (s, 3H) 1024

MS (ESI) m/z 701.10 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H),8.39 (s, 1H), 8.35 (s, 1H), 7.58 (dd, J = 8.9, 2.3 Hz, 1H), 7.44 (s,2H), 7.34 (d, J = 8.9 Hz, 1H), 4.39 (t, J = 9.5 Hz, 2H), 4.26 (t, J =4.5 Hz, 2H), 3.21 (s, 3H), 2.64 (s, 3H), 1.82 (s, 3H) 1022

MS (ESI) m/z 681.06. [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.62 (bs,1H), 8.59 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 7.58 (dd, J = 2.48, 8.88Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H),7.43 (s, 1H), 7.34 (d, J = 8.96 Hz,1H), 4.39 (t, J = 4.39 Hz, 2H), 4.26 (t, J = 4.12 Hz, 2H), 2.71 (s, 6H),2.29 (s, 3H), 1.81 (s, 1H) 1023

MS (ESI) m/z 681.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H),8.39 (s, 1H), 8.34 (s, 1H), 7.58 (dd, J = 8.88, 2.56 Hz, 1H), 7.44 (d, J= 2.84 Hz, 2H), 7.35 (d, J = 8.92 Hz, 1H), 4.39 (t, J = 9.4 Hz, 2H),4.26 (t, J = 8.32 Hz, 2H), 2.71 (s, 3H), 2.57 (s, 3H), 2.30 (s, 3H),1.81 (s, 3H) 1048

MS (ESI) m/z 621.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) ) δ 13.49 (bs,1H), 8.34 (s, 1H), 7.76 (s, 1H), 7.65-7.34 (m, 5H), 4.39 (t, J = 5.8 Hz,2H), 4.23 (t, J = 5.2 Hz, 2H), 2.69 (s, 3H), 2.20-2.09 (m, 1H), 1.85 (s,3H), 1.25-1.18 (m, 2H), 0.97-0.88 (m, 2H) 1040

MS (ESI) m/z 650.13 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.54 (bs,1H), 8.34 (s, 1H), 7.59-7.52 (m, 1H), 7.50-7.45 (m, 5H), 7.40 (bs, 2H),7.35 (d, J = 8.92 Hz, 1H), 6.99 (s, 1H), 4.36 (t, J = 5.24 Hz, 2H), 4.18(t, J = 4.84 Hz, 2H), 2.71 (s, 3H), 2.70 (s, 6H), 1.79 (s, 3H) 1047

MS (ESI) m/z 619.12 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H),8.37 (s, 1H), 7.66 (s, 1H), 7.57 (dd, J = 2.32 Hz, J = 6.64 Hz, 1H),7.41-7.34 (m, 3H), 4.37 (bs, 2H), 4.33-4.28 (m, 1H), 4.22 (bs, 2H),2.81-2.73 (m, 2H), 2.69 (s, 3H), 2.50-2.48 (m, 2H), 2.10-2.03 (m, 1H),2.01-1.84 (m, 1H), 1.84 (s, 3H) 1061

MS (ESI) m/z 672.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (bs,1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.88 (dd, J = 8.56, 2.16 Hz, 1H), 7.87(s, 1H), 7.59 (dd, J = 8.88, 2.16 Hz, 1H), 7.42 (s, 2H), 7.36 (d, J =8.88 Hz, 1H), 7.03 (d, J = 8.52 Hz, 1H), 4.40 (t, J = 5.56 Hz, 2H), 4.25(t, J = 5.20 Hz, 2H), 3.95 (s, 3H), 2.71 (s, 3H), 1.89 (s, 3H) 1050

MS (ESI) m/z 605.09 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.51 (bs,1H), 8.34 (s, 1H), 7.68 (s, 1H), 7.58 (dd, J = 8.64, 1.96 Hz, 1H),7.44-7.38 (m, 2H), 7.35 (d, J = 8.92 Hz, 1H), 4.37 (s, 2H), 4.21 (s,2H), 2.69 (s, 3H), 2.08-2.03 (m, 1H), 1.84 (s, 3H), 1.26-1.20 (m, 2H),0.92-0.86 (m, 2H) 1054

MS (ESI) m/z 650.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H),8.42 (s, 1H), 7.65 (s, 1H), 7.59 (dd, J = 10.96 Hz, 8.88 Hz, 1H),7.33-7.41 (m, 3H), 5.02 (s, 1H), 4.44 (s, 1H), 4.36 (bs, 2H), 4.19 (bs,2H), 3.74-3.79 (m, 2H), 3.43-3.47 (m, 1H), 3.33 (s, 1H), 2.69 (s, 3H),2.07-2.15 (m, 1H), 1.75-1.86 (m, 1H), 1.80 (s, 3H) 1083

MS (ESI) m/z 686.21 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H),7.98 (s, 1H), 7.67 (s, 1H), 7.59 (dd, J = 2.52 Hz, J = 8.84 Hz, 1H),7.43 (bs, 2H), 7.35 (d, J = 8.96 Hz, 1H), 4.39 (t, J = 6.20 Hz, 2H),4.23 (t, J = 6.32 Hz, 2H), 3.56 (d, J = 9.80 Hz, 2H), 3.25-3.13 (m, 6H),2.99 (q, J = 7.52 Hz, J = 15.04 Hz, 2H), 2.93 (bs, 3H), 1.79 (s, 3H),1.35 (t, 7.56 Hz, 3H) 1077

MS (ESI) m/z, 580.08 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.85 (s,1H), 8.50 (s, 1H), 7.58 (dd, J = 2.56, 11.44 Hz, 1H), 7.48 (d, J = 1.76Hz, 1H), 7.42-7.41 (m, 2H), 7.34 (d, J = 8.96 Hz, 1H), 7.23 (d, J = 2.56Hz, 1H), 7.18 (bs, 2H), 4.35 (t, J = 5.28 Hz, 2H), 4.24 (t, J = 4.76 Hz,2H), 2.99 (q, J = 7.48 Hz, 2H), 1.34 (t, J = 7.52 Hz, 3H) 1078

MS (ESI) m/z 581.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.75 (bs,1H), 8.53 (s, 1H), 7.72 (d, J = 1.60 Hz, 1H), 7.58 (dd, J = 2.56, 8.88Hz, 1H), 7.46 (bs, 1H), 7.42 (d, J = 2.56 Hz, 2H), 7.34 (d, J = 8.96 Hz,1H), 7.30 (d, J = 1.76 Hz, 1H), 4.35 (t, J = 5.16 Hz, 2H), 4.10 (t, J =5.04 Hz, 2H), 2.99 (q, J = 7.48 Hz, 2H), 1.34 (t, J = 7.56 Hz, 3H) 1090b

MS (ESI) m/z 689.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.28 (bs,1H), 7.58 (dd, J = 2.28, 8.84 Hz, 1H), 7.41 (bs, 1H), 7.38 (d, J = 2.36Hz, 1H), 7.34 (d, J = 8.92 Hz, 1H), 6.99 (d, J = 8.28 Hz, 1H), 4.38 (t,J = 5.04 Hz, 2H), 4.19 (t, J = 4.68 Hz, 2H), 3.55 (d, J = 11.64 Hz, 2H),2.79-2.73 (m, 2H), 2.70 (s, 3H), 2.39 (s, 3H), 2.37-2.34 (m, 2H), 2.23(s, 3H), 1.86 (s, 3H), 1.10 (d, J = 6.00 Hz, 6H) 1084

MS (ESI) m/z 687.16 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.72 (bs,1H), 8.30 (s, 1H), 8.10 (s, 1H), 7.59 (dd, J = 2.5, 9.1 Hz, 1H), 7.45(s, 2H), 7.34 (d, J = 8.9 Hz, 1H), 4.38 (bs, 2H), 4.21 (bs, 2H), 3.59(bs, 4H), 3.25 (bs, 4H), 3.03- 2.97 (m, 2H), 2.90 (s, 3H), 1.72 (s, 3H),1.34 (t, J = 7.52 Hz, 3H) 1090a

MS (ESI) m/z 705.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.28 (bs,1H), 7.60 (bs, 1H), 7.58 (dd, J = 2.64, 8.96 Hz, 1H), 7.39 (bs, 1H),7.38 (d, J = 2.60 Hz, 1H), 7.35 (d, J = 9.00 Hz, 1H), 4.37 (t, J = 4.56Hz, 2H), 4.23 (t, J = 4.16 Hz, 2H), 3.17-3.12 (m, 5H), 2.70 (s, 3H),2.43-2.38 (m, 4H), 2.22 (s, 3H), 1.96 (s, 3H), 1.03 (d, J = 6.08 Hz, 6H)1096

MS (ESI) m/z 687.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.36 (bs,1H), 8.00 (s, 1H), 8.32 (s, 1H), 7.60 (dd, J = 2.20, 8.68 Hz, 1H), 7.41(s, 1H), 7.34 (d, J = 8.92 Hz, 1H), 4.40 (t, J = 4.32 Hz, 2H), 4.20 (t,J = 3.92 Hz, 2H), 3.23 (bs, 4H), 2.69 (s, 3H), 2.49 (bs, 4H), 2.35 (s,3H), 2.23 (s, 3H), 1.77 (s, 3H) 1094

MS (ESI) m/z 675.07 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H),8.38 (s, 1H), 7.58 (s, 2H), 7.41-7.33 (m, 3H), 4.36 (s, 2H), 4.21 (s,2H), 3.55 (bs, 4H), 3.24 (bs, 2H), 3.06 (bs, 2H), 2.91 (s, 3H), 2.69 (s,3H), 1.82 (s, 3H) 1095

MS (ESI) m/z 711.15 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H),7.57 (dd, J = 8.8, 2.5 Hz, 1H), 7.45-7.41 (m, 2H), 7.36-7.32 (m, 2H),7.12 (d, J = 13.2 Hz, 1H), 4.35 (t, J = 9.2 Hz, 2H), 4.20 (t, J = 9.3Hz, 2H), 3.14 (bs, 4H), 2.69 (s, 3H), 2.50 (bs, 4H), 1.79 (s, 3H), 1.23(s, 3H) 1138

MS (ESI) m/z 679.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H),8.41 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.61(dd, J = 8.9, 2.7 Hz, 1H), 7.46-7.37 (m, 3H), 4.42 (t, J = 5.1 Hz, 2H),4.25 (t, J = 5.1 Hz, 2H), 3.56 (s, 3H), 3.45-3.37 (m, 2H), 3.37-3.29 (m,2H), 2.91 (d, J = 4.5 Hz, 6H), 2.70 (s, 3H), 1.91 (s, 3H) 1098

MS (ESI) m/z 642.01 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H),8.73 (d, J = 3.7 Hz, 1H), 8.24 (s, 1H), 8.13 (d, J = 7.8 Hz 1H), 7.75(s, 1H), 7.63-7.57 (m, 2H), 7.40-7.35 (m, 3H), 4.42 (t, J = 5.1 Hz, 2H),4.27 (t, J = 4.8 Hz, 2H), 2.69 (s, 3H), 1.83 (s, 3H) 1114

MS (ESI) m/z 683.3 [M + 1]+; 1H NMR (400 MHz, Chloroform-d) δ 8.79 (d, J= 4.9 Hz, 1H), 8.66 (d, J = 0.9 Hz, 1H), 8.30 (s, 1H), 7.48 (dd, J =8.9, 2.6 Hz, 1H), 7.32 (d, J = 4.9 Hz, 1H), 7.24 (d, J = 2.6 Hz, 1H),7.07 (d, J = 8.9 Hz, 1H), 6.87 (d, J = 0.9 Hz, 1H), 5.23-5.13 (m, 1H),4.37 (t, J = 5.0 Hz, 2H), 4.28 (t, J = 5.0 Hz, 2H), 3.88 (d, J = 12.0Hz, 2H), 3.57 (t, J = 14.3 Hz, 2H), 3.34-3.24 (m, 2H), 2.97 (s, 3H),2.51-2.36 (m, 2H), 2.08-2.02 (m, 5H), 1.80 (t, J = 19.0 Hz, 3H) 1155

MS (ESI) m/z 735.80 [M + 1]; 1H NMR (400 MHz, DMSO-d6) δ 12.50 (bs, 1H),8.87 (d, J = 4.7 Hz, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.60 (dd, J = 2.4,8.9 Hz, 1H), 7.53 (d, J = 4.7 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.35(d, J = 8.9 Hz, 1H), 4.39 (t, J = 5.1 Hz, 2H), 4.20 (t, J = 4.5 Hz, 2H),3.51 (s, 3H), 3.28 (bs, 4H), 2.55 (bs, 4H), 2.28 (s, 3H), 1.69 (s, 3H)1147

MS (ESI) m/z 460.1 [M + 1]+; 1H NMR (300 MHz, DMSO-d6) δ 12.95 (s, 1H),8.00-7.82 (m, 5H), 7.56-7.49 (m, 1H), 7.45-7.36 (m, 2H), 7.29 (d, J =2.7 Hz, 1H), 7.21 (d, J = 8.9 Hz, 1H), 4.34 (s, 4H), 2.19 (s, 3H) 1150

MS (ESI) m/z 721.29 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H),9.78 (s, 1H), 8.12 (s, 1H), 7.62 (dd, J = 8.8, 2.5 Hz, 1H), 7.45- 7.42(m, 2H), 7.38 (d, 1H), 4.41 (t, J = 4.5 Hz, 2H), 4.26 (t, J = 8.9 Hz,2H), 3.90 (m, 2H), 3.57 (s, 5H), 3.23 (m, 4H), 2.90 (s, 3H), 2.72 (s,3H), 2.47 (s, 3H), 1.99 (s, 3H) 1205

MS (ESI) m/z 661.24 [M + 1]+. 1H NMR (400 MHz, DMSO-d6) δ 14.29 (bs,1H), 7.58 (d, J = 6.8 Hz, 1H), 7.44-7.34 (m, 4H), 4.38 (t, J = 4.8 Hz,2H), 4.26 (t, J = 5.2 Hz, 2H), 2.68 (s, 3H), 2.54 (s, 3H), 2.52-2.45 (m,8H), 2.24 (s, 3H), 1.98 (s, 3H) 1193

MS (ESI) m/z 639.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H),7.59-7.58 (m, 6H), 7.42-7.36 (m, 3H), 4.41 (t, J = 4.0 Hz, 2H), 4.25 (t,J = 4.0, Hz, 2H), 3.20 (s, 3H), 2.66 (s, 3H), 2.03 (s, 3H) 1201

MS (ESI) m/z 719.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.24 (bs,1H), 7.65 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.37-7.33 (m, 3H), 4.38 (s,2H), 4.26 (s, 2H), 2.68 (s, 6H), 2.5-2.47 (m, 8H), 1.93 (s, 3H), 1.06(s, 9H) 1210

MS (ESI) m/z 672.17 [M + 1]+; 1H NMR (400 MHz, DMSO-d6), δ 8.79 (d, J =4.8 Hz, 1H), 8.02 (s, 1H), 7.68 (s, 1H), 7.59 (dd, J = 9.2 Hz, 2.4 Hz,1H), 7.51 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.35 (d, J =9.2 Hz, 1H), 4.40 (bs, 2H), 4.24 (bs, 2H), 3.56-3.54 (m, 2H), 3.20- 3.12(m, 6H), 2.93 (s, 3H), 2.23 (s, 3H), 1.78 (s, 3H) 1208

MS (ESI) m/z 673.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.41 (bs,1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.41 (s, 1H), 7.40-7.32 (m, 2H),6.96 (s, 1H), 4.39 (s, 2H), 4.19 (s, 2H), 4.00 (s, 3H), 3.26 (s, 4H),2.71 (s, 3H), 2.55-2.45 (merged, 4H), 2.40 (s, 3H), 2.28 (s, 3H), 1.91(s, 3H) 1209

MS (ESI) m/z 682.30 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H),7.96 (s, 1H), 7.93 (s, 1H), 7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.42- 7.34(m, 3H), 4.39 (s, 2H), 4.22 (s, 2H), 3.52 (s, 3H), 3.04 (s, 4H), 2.68(s, 3H), 2.50 (merged, 4H), 2.26 (s, 3H), 1.87 (s, 3H) 1240

MS (ESI) m/z 682.34 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.14 (bs,1H), 8.82 (d, J = 4.8, 1H), 8.32 (s, 1H), 8.05 (s, 1H), 7.57 (d, J = 6.4Hz, 1H), 7.42 (d, J = 5.2 Hz, 2H), 7.35 (d, J = 9.2 Hz, 1H), 6.07 (s,1H), 4.39 (s, 2H), 4.19 (s, 2H), 3.67 (bs, 4H), 2.87 (bs, 4H), 2.23 (s,3H), 1.61 (s, 3H) 1211

MS (ESI) m/z 656.26 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H),8.27 (s, 1H), 8.08 (s, 1H), 7.56 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.40 (s,1H), 7.33 (s, 1H), 7.30 (d, J = 14.8 Hz, 1H), 7.25 (s, 1H), 4.53-3.38(m, 4H), 4.25-3.16 (m, 4H), 3.01-2.98 (m, 2H), 2.89 (s, 3H), 2.86 (s,3H), 2.69-2.60 (m, 2H), 2.26 (s, 3H) 1230

MS (ESI) m/z 660.24 [M + 2]+; 1H NMR (400 MHz, DMSO-d6), δ 8.1 (d, J =4.8 Hz, 1H), 8.30 (s, 1H), 7.95 (s, 1H), 7.70 (s, 1H), 7.58 (dd, J =8.8, 2.4 Hz, 1H), 7.45-7.42 (m, 2H), 7.34 (d, J = 9.2 Hz, 1H), 4.38 (bs,2H), 4.23 (bs, 2H), 3.0 (bs, 8H), 2.50 (bs, 3H), 1.78 (bs, 3H) 1278

MS (ESI) m/z 672.23 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.29 (bs,1H), 8.81 (d, J = 4.8 Hz, 1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.58 (dd, J =8.8, 6.4 Hz 1H), 7.52-7.15 (m, 4H), 4.59 (d, J = 47.2 Hz, 2H), 4.40 (s,2H), 4.23 (s, 2H), 3.76 (s, 2H), 2.89-2.71 (m, 2H), 2.30 (s, 3H), 1.79(s, 3H) 1267

MS (ESI) m/z 683.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.14 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.54 (s, 1H), 8.52 (d, J = 2.8 Hz, 1H),7.91 (s, 1H), 7.62-7.55 (m, 2H), 7.46-7.43 (m, 2H), 7.30 (d, J = 8.9 Hz,1H), 4.66-4.56 (m, 2H), 4.22 (s, 2H), 4.15-4.06 (m, 2H), 2.96 (s, 6H),2.06 (s, 3H), 1.77 (s, 3H) 1277

MS (ESI) m/z 688.19 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.38 (s, 1H), 7.76 (s, 1H), 7.59 (dd, J = 2.4, 8.8 Hz, 1H),7.50-7.20 (m, 4H), 4.39 (d, J = 4.4 Hz, 2H), 4.23 (bs, 2H), 4.05 (s,2H), 3.85 (t, J = 12.4 Hz, 4H), 1.78 (s, 3H) 1285

MS (ESI) m/z 696.35 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.93 (bs,1H), 8.78 (d, J = 4.8 Hz, 1H), 8.10 (s, 1H), 7.59 (dd, J = 8.8 Hz, 2.8Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.36 (d, J= 8.8 Hz, 1H), 6.13 (s, 1H), 4.41 (bs, 2H), 4.22 (bs, 2H), 3.93-3.87 (m,2H), 3.54 (d, J = 10.8 Hz, 2H), 3.16 (d, J = 12.8 Hz, 2H), 3.09-3.06 (m,2H), 2.90 (s, 3H), 2.37 (s, 3H), 1.70 (s, 3H) 1280

MS (ESI) m/z 616.25 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H),7.58 (dd, J = 8.8, 2.4 Hz, 1H), 7.44-7.31 (m, 5H), 4.46-4.34 (m, 3H),4.19 (s, 2H), 3.87-3.77 (m, 2H), 3.54 (t, J = 7.20, 1H), 3.36 (d, J =10.4 Hz, 1H), 2.70 (s, 3H), 2.08-1.86 (m, 2H), 1.78 (s, 3H) 1284

MS (ESI) m/z 697.27 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.00 (bs,1H), 10.10 (bs, 1H), 8.77 (d, J = 4.8 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H),7.96 (s, 1H), 7.64-7.54 (m, 2H), 7.47-7.46 (m, 2H), 7.29 (d, J = 8.9 Hz,1H), 4.65-4.56 (m, 2H), 4.23 (s, 2H), 4.15-4.10 (m, 2H), 2.94 (s, 6H),2.57 (s, 3H), 2.06 (s, 3H), 1.83 (s, 3H) 1295

MS (ESI) m/z 707.34 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.58 (bs,1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.61-7.58 (dd, J = 2.8, 8.8 Hz, 1H),7.42 (s, 2H), 7.38 (d, J = 9.2 Hz, 1H), 4.41 (t, J = 4.8 Hz, 2H), 4.24(t, J = 4.4 Hz, 2H), 3.74 (bs, 2H), 3.57 (s, 3H), 3.08 (bs, 4H), 2.87(m, 2H), 2.71 (s, 3H), 2.32 (s, 3H), 1.87 (s, 3H) 1290

MS (ESI) m/z 703.31 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =4.8 Hz, 1H), 8.62 (s, 1H), 8.25 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.69(t, J = 3.2 Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 6.43 (t, J = 54.4 Hz,1H), 4.85 (s, 2H), 3.44 (s, 6H), 3.18 (bs, 4H), 2.09 (s, 3H) 1294

MS (ESI) m/z 707.32 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 14.03 (bs,1H), 9.79 (bs, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.13 (s, 1H), 7.63-7.60(dd, J = 2.4, 8.8 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.44 (d, J = 2.4Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 4.42 (bs, 2H), 4.25 (bs, 2H), 3.93(t, J = 12.0 Hz, 2H), 3.59-3.57 (m, 5H), 3.34-23 (m, 4H), 2.91 (s, 3H),2.44 (s, 3H), 1.88 (s, 3H) 1300

MS (ESI) m/z 735.80 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.50 (bs,1H), 8.87 (d, J = 4.7 Hz, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.60 (dd, J =2.4, 8.9 Hz, 1H), 7.53 (d, J = 4.7 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H),7.35 (d, J = 9.0 Hz, 1H), 4.39 (t, J = 5.1 Hz, 2H), 4.20 (t, J = 4.6 Hz,2H), 3.51 (s, 3H), 3.28 (bs, 4H), 2.55 (bs, 4H), 2.28 (s, 3H), 1.69 (s,3H) 1296

MS (ESI) m/z 693.35; 1H NMR (400 MHz, DMSO-d6) δ 13.50 (bs, 1H), 9.78(bs, 1H), 8.84 (d, J = 4.8 Hz, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.61(dd, J = 8.4, 2.4, Hz, 1H), 7.49 (d, J = 4.7 Hz, 1H), 7.44 (d, J = 2.4Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 4.49-4.39 (m, 2H), 4.30-4.20 (m, 2H),3.95-3.85 (m, 2 Hz), 3.62-3.50 (m, 5H), 3.40 (d, J = 12.0 Hz, 2H), 3.29-3.19 (m, 2H), 2.92 (s, 3H), 1.79 (s, 3H) 1299

MS (ESI) m/z 735.36 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.58 (bs,1H), 8.83 (d, J = 4.8 Hz, 1H), 8.36 (s, 1H), 7.97 (s, 1H), 7.74 (s, 1H),7.56 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.8 Hz,1H), 4.39 (s, 2H), 4.22 (s, 2H), 3.42 (s, 2H), 3.31 (m, 4H), 2.95 (m,4H), 2.10 (s, 3H), 1.77 (s, 3H) 1379

MS (ESI) m/z 602.3 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H),8.16 (s, 1H), 7.66-7.51 (m, 2H), 7.49- 7.33 (m, 3H), 4.63 (s, 2H), 4.42(t, J = 5.1 Hz, 2H), 4.25 (t, J = 5.0 Hz, 2H), 2.96 (s, 6H), 2.73 (s,3H), 2.62 (s, 3H), 1.90 (s, 3H) 1331

MS (ESI) m/z 596.2 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.39 (bs, 1H),9.59 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.44(s, 1H), 7.60-7.57 (dd, J = 2.4, 8.8 Hz, 1H), 7.44 (t, J = 8.3 Hz, 2H),7.33 (d, J = 8.8 Hz, 1H), 4.34 (d, J = 4.4 Hz, 2H), 4.19 (s, 2H), 3.43(s, 4H), 2.90 (s, 6H), 1.83 (s, 3H) 1373

MS (ESI) m/z 535.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J =4.8 Hz, 1H), 8.44 (s, 1H), 7.99 (dd, J = 8.4, 4.5 Hz, 1H), 7.77 (dd, J =9.6, 8.4 Hz, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.49 (d, J = 4.8 Hz,1H), 7.43 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.42 (t, J =5.1 Hz, 2H), 4.26 (t, J = 5.1 Hz, 2H), 1.87 (s, 3H) 1387

MS (ESI) m/z 676.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J =2.6 Hz, 1H), 8.57 (s, 1H), 8.40 (s, 1H), 8.04 (ddd, J = 9.4, 2.8, 1.7Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J = 8.9, 2.7 Hz, 1H), 7.47-7.32 (m,3H), 6.93 (t, J = 53.7 Hz, 1H), 4.42 (t, J = 5.0 Hz, 2H), 4.29 (dd, J =5.3, 1.9 Hz, 2H), 2.73 (s, 3H), 1.92 (s, 3H) 1385

MS (ESI) m/z 686.1 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H),7.95 (s, 1H), 7.63-7.51 (m, 3H), 7.44- 7.40 (m, 2H), 7.36 (d, J = 9.0Hz, 1H), 6.90 (t, J = 53.7 Hz, 3H), 4.42 (t, J = 5.0 Hz, 2H), 4.28 (t, J= 5.0 Hz, 2H), 2.72 (s, 3H), 2.66 (s, 6H), 1.89 (s, 3H) 1386

MS (ESI) m/z 672.0 [M + 1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J =5.4 Hz, 1H), 8.39 (s, 1H), 7.95 (s, 1H), 7.62- 7.57 (m, 2H), 7.56-7.51(m, 1H), 7.44- 7.40 (m, 2H), 7.36 (d, J = 9.0 Hz, 1H), 6.88 (t, J = 53.8Hz, 1H), 4.41 (t, J = 5.0 Hz, 2H), 4.28 (t, J = 4.8 Hz, 2H), 2.72 (s,3H), 2.65 (s, 3H), 1.89 (s, 3H) 1935

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MS (ESI) m/z 526.15 [M + 1]+ 2035

MS (ESI) m/z 553.33 [M + 1]+

Example 5. Biological Studies Example 5A. Fluorescence Polarization

Compounds were screened for eIF4E binding potency using a fluorescencepolarization competition assay. All binding reactions were performed influorescence polarization buffer (FPB) containing 20 mM Tris pH 7.5, 100mM NaCl, 1 mM DTT, and 0.02% Tween-20. Final binding reactions contained75 nM recombinant eIF4E (Beryllium, custom order), 20 nMEDA-m⁷GDP-ATTO-550 (Jena Bioscience, NU-827-550) and varyingconcentrations of the inhibitory compound of interest. Final DMSOconcentration in each reaction was 1%.

eIF4E protein was pre-incubated with EDA-m⁷GDP-ATTO-550 in FPB at 2×concentrations for 5 minutes prior to the addition of compounds.Compounds (100×) were prepared using 3-fold serial dilutions in 100%DMSO, and subsequently diluted 1:50 in FPB to produce 2× stocks. 50 μlof 2× eIF4E/EDA-m⁷GDP-ATTO-550 were transferred to the wells of a96-well half-area black flat bottom polystyrene plate. 50 μl of 2× testcompound were added, and binding reactions were allowed to equilibratefor 30 minutes at room temperature while protected from light. Thefluorescent polarization signal was detected using a Victor 2multi-label counter (Perkin Elmer) and the concentration necessary toachieve inhibition of eIF4E/EDA-m⁷GDP-ATTO-550 binding by 50% (IC₅₀) wascalculated using data from an 8-point compound dilution series.

The results of these assays are set forth in Tables 4A and 4B, below. InTable 4A, IC₅₀ values of less than 0.05 μM are labelled as “+++”, from 1to 0.05 μM are labelled as “++”, and greater than 1 μM are labelled as“+”. Calculated IC₅₀ values are shown in Table 4B. ND=not determined.

TABLE 4A elF4E Compound FP    1 ++    2 +    3 +    4 +    5 +    6 +   7 +    8 +++    9 +   10 +   11 +   12 +   13 +   14 +   15 +   16++++   17 ++   18 ++   19 ++   20 +   21 ++   22 +++   23 ++   24 ++  25 +   26 ++   27 ++   28 ++   29 ++   30 ++   31 ++   32 ++   33 ++  34 ++   35 +++   36 ND   37 +++   38 ++   39 ++   40 +++   41 +   42 +  43 +   44 ++   45 +   46 ++   47 +++   48 ++   49 +++   50 +++   51+++   52 +   53 ++   54 +   55 +++   56 +++   57 +++   58 ++   59 +++  60 +++   61 +++   62 +++   63 +++   64 ++   65 +++   66 ++   67 +  68 +   69 +   70 ++   71 ++   72 +   73 ++   74 ++   75 +   76 +  77 +   78 +   79 +   80 ++   81 +   82 +   83 +   84 +   85 +   86 +  87 +   88 +   89 +   90 +   91 ++   92 +   93 +   94 +   95 +   96 +  97 +   98 ++   99 +  100 +  101 +  102 +  103 ++  104 ++  105 +  106 + 107 +  108 +  109 +  110 +  111 ++  112 +  113 ++  114 ++  115 +  116 + 117 +  118 ++  119 +++  120 +++  121 +++  122 +++  123 +++  124 + 125 +  126 +  127 ++  128 ++  129 +  130 +  131 ++  132 ++  133 ++  134++  135 ND  136 ++  137 ++  138 ++  139 +++  140 ++  141 +++  142 ++ 143 +++  144 +++  145 ++  146 ++  147 +++  148 +++  149 ++  150A ++ 150B ++  150C ++  151 +++  152 +++  153 ++  154 ++  155 +++  156 +++ 157 ND  158 +++  159 +++  160 +++  161 ++  162 +++  163 ++  164 ND  165++  166 +++  167 ++  168 +++  169 ++  170 ++  171 ++  172 ++  173 ++ 174 ++  175 +++  176 +++  177 +++  178 ++  179 +++  180 +++  181 ++ 182 +++  183 ++  184 ++  185 ++  186 ++  187 +++  188 ++  189 +  190 ++ 191 ++  192 +  193 +++  194 +++  195 +++  196 +++  197 ++  198 ++  199++  200 +++  201 ++  202 +++  203 ++  204 +++  205 ++  206 ++  207 +++ 208 ++  209 +++  210 ++  211 +++  212 +++  213 +++  214 +++  215 ++ 216 ++  217 ++  218 +++  219 ++  220 ++  221 ++  222 ++  223 ++  224+++  225 ++  226 ++  227 ++  228 +++  229 +++  230 +++  231 +++  232 +++ 233 +++  234 +++  235 +++  236 +++  237 ++  238 +++  239 +++  240 +++ 241 +++  242 +++  243 +++  244 +++  245 +++  246 +++  247 ++  248 ++ 249 +++  250 +++  251 +++  252 +++  253 +++  254 +++  255 ++  256 ++ 257 ++  258 +++  259 ++  260 +++  261 +++  262 +++  263 +++  264 +++ 265 ++  266 +++  267 ++  268 +++  269 +++  270 +++  271 +++  272 +++ 273 +++  274 +++  275 +++  276 +++  277 +++  278 +++  279 +++  280 +++ 281 +++  282 +++  283 +++  284 +++  285 ++  286 ++  287 +++  288 +++ 289 +++  290 +++  291 ++  292 ++  293 ++  294 +++  295 ++  296 +++  297+++  298 ++  299 +++  300 +++  301 ++  302 ++  303 ++  304 +  305 ++ 306 ++  307 ++  308 ++  309 ++  310 ++  311 ++  312 ++  313 +++  314+++  315 ++  316 +++  317 +++  318 +++  319 ++  320 +++  321 +++  322 ++ 323 ++  324 ++  325 ++  326 +  327 +++  328 +  329 +++  330 +++  331 ND 332 +++  333 ND  334 +++  335 ++  336 +++  337 +++  338 +++  339 +++ 340 +++  341 +++  342 +++  343 +++  344 +++  345 +++  345 +++  346 +++ 347 +++  348 +++  349 +++  350 +++  351 ++  351 ++  352 +  353 ++  354++  355 ++  356 +  357 +++  358 ++  359 +++  360 +++  361 ++  362 ++ 363 +++  364 ++  365 +++  366 +++  367 +++  368 +++  369 +++  370 +++ 371 +++  372 +++  373 +++  374 +++  375 ++  376 +++  377 ++  378 +++ 379 +++  380 +++  381 ND  382 ND  383 ND  384 +++  385 +++  386 +++ 387 ++  388 +++  389 +++  390 +++  391 +++  392 +++  393 +++  394 +++ 395 +++  396 +++  397 +++  398 ++  399 ++  400 +++  401 +++  402 ++ 403 +++  404 +++  405 +++  406 +++  407 +++  408 +++  409 +++  410 ++ 411 ++  412 ++  413 +++  414 +++  415 +++  416 +++  417 +++  418 +++ 419 +++  420 +++  421 +++  422 +++  423 +++  424 +++  425 +++  426 +++ 427 +++  428 +++  429 +++  430 +++  431 ++  432 +++  433 +++  434 +++ 435 +++  436 +++  437 +++  438 +++  439 +++  439 +++  440 +++  441 +++ 442 +++  443 ++  444 +++  445 ++  446 ++  447 ++  448 +++  449 +++  450+++  451 +++  452 +++  453 +  454 ++  455 ++  456 +++  457 +++  458 +++ 459 +++  460 +++  461 +++  462 +++  463 +++  464 +++  465 +++  466 +++ 467 +++  468 +++  469 +++  470 +++  471 +++  472 +++  473 +++  474 +++ 475 +++  476 +++  477 +++  478 +++  479 +++  480 +++  481 +++  482 +++ 483 +++  484 +++  485 +++  486 +++  487 ++  488 +++  489 +++  490 ++ 491 +++  492 +++  493 ++  494 ++  495 ++  496 +  497 +++  498 +++  499++  500 +++  501 +++  502 +++  503 +++  504 +++  505 +++  506 ++  507+++  508 +++  509 ++  510 ++  511 ++  512 ++  513 +++  514 +++  515 +++ 516 +++  517 +++  518 +++  519 +++  520 +++  521 ++  522 +++  523 +++ 524 +++  525 +++  526 ++  527 +++  528 +++  529 +++  530 +++  531 +++ 532 +++  533 ++  534 +++  535 ++  536 +++  537 +++  538 +++  539 +++ 540 +++  541 +++  542 +++  543 +++  544 +++  545 +++  546 +++  547 ++ 548 +++  549 +++  550 ++  551 +++  552 ++  553 +++  554 +++  555 +++ 556 +++  557 +++  558 +++  559 +++  560 +++  561 ++  562 +++  563 +++ 564 +++  565 +++  566 +++  567 +++  568 +++  569 +++  570 +++  571 ++ 572 +++  573 ++  574 ++  575 +++  576 +++  577 +++  578 +++  579 +++ 580 +++  581 +++  582 +++  583 +++  584 +++  585 +++  586 +++  587 +++ 588 +++  589 +++  590 +++  591 +++  592 +++  593 +++  594 +  595 +++ 596 +++  597 +++  598 ++  599 ++  600 +++  601 ++  602 +++  603 +++ 604 ++  605 ND  606 +++  607 +++  608 +++  609 +++  610 +++  611 +++ 612 +++  613 +++  614 ++  615 +++  616 +++  617 +++  618 +++  619 +++ 620 +++  621 ++  622 +++  623 +++  624 +++  625 ++  626 +++  627 +++ 628 +++  629 +++  630 ++  631 +++  632 +++  633 +++  634 +++  635 +++ 636 +++  637 +++  638 +++  639 +++  640 +++  641 +++  642 +++  643 +++ 644 +++  645 +++  646 +++  647 +++  648 +++  649 +++  650 +++  651 +++ 652 +++  653 +++  654 +++  655 +++  656 +++  657 +++  658 +  659 +++ 660 ++  661 +++  662 ++  663 ++  664 ++  665 +++  666 ++  667 +++  668+++  669 +++  670 +++  671 ++  672 ++  673 +++  674 +++  675 +++  676+++  677 +++  678 ++  679 ++  680 ++  681 +++  682 +++  683 +++  684 +++ 685 +++  686 +++  687 +++  688 +++  689 +++  690 +++  691 +++  692 +++ 693 +++  694 +++  695 +++  696 +++  697 +++  698 +++  699 +++  700 +++ 701 +++  702 +++  703 +++  704 ++  705 +++  706 ++  707 +++  708 ++ 709 ++  710 +++  711 ++  712 +++  713 +++  714 +++  715 ND  716 ND  717++  718 +++  719 +++  720 ++  721 +++  722 +++  723 +++  724 +++  725+++  726 ++  727 +++  728 +++  729 ++  730 ++  731 +++  732 ++  733 + 734 +++  735 ++  736 +++  737 +++  738 +++  739 +++  740 +++  741 +++ 742 +++  743 ++  744 +++  745 +++  746 +++  747 +++  748 +++  749 + 750 +++  751 ++  752 +++  753 +++  754 +++  755 +++  756 +++  757 ++ 758 +++  759 ++  760 +++  761 +++  762 +++  763 +++  764 +++  765 +++ 766 +++  767 +++  768 +++  769 +++  770 +++  771 +++  772 +++  773 +++ 774 +++  775 +++  776 +++  777 ++  778 +++  779 +++  780 +++  781 +++ 782 +++  783 +++  784 +++  785 +++  786 +++  787 +++  788Fa +  788Fb+++  789 +++  790 +++  791 +++  792 +++  793 +++  794 +++  795 +++  796+++  797 +++  798 +++  799 +++  800 +++  801 +++  802 +++  803 ++  804+++  805 +++  806 +++  807 +++  808 ++  809 +++  810 +++  811 ++  812+++  813 +++  814 ND  815 +++  816 +++  817 +++  818 +++  819 +++  820+++  821 +++  822 +++  823 +++  824 +++  825 +++  826 +++  827 +++  828+++  829 +++  830 +++  831 +++  832 ND  833 ++  834 +++  835 +++  836+++  837 +++  838 +++  839 +++  840 +++  841 ++  842 +++  843 +++  844+++  845 +++  846 +++  847 +++  848 +++  849 +++  850 +++  851 +++  852+++  853 +++  854 +++  855 +++  856 +++  857 +++  858 +++  859 +++  860+++  861 +++  862 +++  863 +++  864 +++  865 +++  866 +++  867 +++  868+++  869 +++  870 ++  871 +++  872 +++  873 +++  874 +++  875 +++  876++  877 ++  878 +++  879 +++  880 ++  881 +++  882 +++  883 +++  884 +++ 885 +++  886 +++  887 +++  888 +++  889 +++  890 +++  891 +++  892 +++ 893 +++  894 +++  895 +++  896 +++  897 +++  898 +++  899 +++  900 +++ 901 +++  902 +++  903 +++  904 +++  905 +++  906 +++  907 +++  908 +++ 909 +++  910 +++  911 +++  912 +++  913 +++  914 +++  915 +++  916 +++ 917 +++  918 +++  919 +++  920 +++  921 ++  922 ++  923 +++  924 +++ 925 +++  926 +++  927 +++  928 +++  929 +++  930 +++  931 +++  932 +++ 933 ++  934 +++  935 +++  936 ND  937 +++  938 +++  939 +++  940 ++ 941 +++  942 +++  943 +++  944 +++  945 +++  946 +++  947 +++  948 +++ 949 +++  950 +++  951 +++  952 +++  953 +++  954 +++  955 +++  956 +++ 957 +++  958 +++  959 +++  960 +++  961 +++  962 +++  963 +++  964 +++ 965 ++  966 +++  967 +++  968 +++  969 +++  970 ++  971 ++  972 +++ 973 ++  974 +++  975 +++  976 +++  977 +++  978 +++  979 +++  980 +++ 981 +++  982 +++  983 +++  984 +++  985 +++  986 +++  987 +++  988 +++ 989 +++  990 +++  991 +++  992 ++  993 +++  994 +++  995 +++  996 +++ 997 +++  998 +++  999 +++ 1000 +++ 1001 +++ 1002 +++ 1003 +++ 1004 +++1005 +++ 1006 +++ 1007 +++ 1008 +++ 1009 +++ 1010 +++ 1011 +++ 1012 +++1013 +++ 1014 +++ 1015 +++ 1016 +++ 1017 +++ 1018 +++ 1019 +++ 1020 +++1021 +++ 1022 +++ 1023 +++ 1024 +++ 1025 +++ 1026 +++ 1027 +++ 1028 +++1029 +++ 1030 +++ 1031 +++ 1032 +++ 1033 +++ 1034 +++ 1035 +++ 1036 +++1037 +++ 1038 +++ 1039 +++ 1040 +++ 1041 +++ 1042 +++ 1043 +++ 1044 +++1045 +++ 1046 +++ 1047 +++ 1048 +++ 1049 +++ 1050 +++ 1051 +++ 1052 +++1053 +++ 1054 +++ 1055 +++ 1056 +++ 1057 +++ 1058 +++ 1059 +++ 1060 ++1061 +++ 1062 +++ 1063 +++ 1064 +++ 1065 +++ 1066 ++ 1067 +++ 1068 +++1069 +++ 1070 +++ 1071 ++ 1072 +++ 1073 ++ 1074 +++ 1075 +++ 1076 +++1077 ++ 1078 ++ 1079 ND 1080 ++ 1081 + 1082 ++ 1083 +++ 1084 +++ 1085 ++1086 +++ 1087 +++ 1088 ++ 1089 ++ 1090 +++ 1090 ++ 1091 ++ 1092 +++ 1093++ 1094 ++ 1095 +++ 1096 +++ 1097 +++ 1098 +++ 1099 +++ 1100 +++ 1101+++ 1102 +++ 1103 +++ 1104 ++ 1105 +++ 1106 +++ 1107 +++ 1108 +++ 1109+++ 1110 +++ 1111 +++ 1112 +++ 1113 ++ 1114 +++ 1115 +++ 1116 +++ 1117+++ 1118 +++ 1119 +++ 1120 +++ 1121 +++ 1122 +++ 1123 +++ 1124 +++ 1125+++ 1126 +++ 1127 +++ 1128 +++ 1129 +++ 1130 +++ 1131 +++ 1132 +++ 1133+++ 1134 +++ 1135 +++ 1136 +++ 1137 +++ 1138 +++ 1139 ND 1140 +++ 1141+++ 1142 +++ 1143 +++ 1144 +++ 1145 +++ 1146 +++ 1147 +++ 1148 +++ 1149+++ 1150 +++ 1151 +++ 1152 +++ 1153 +++ 1154 +++ 1155 +++ 1156 +++ 1157+++ 1158 +++ 1159 +++ 1160 +++ 1161 +++ 1162 +++ 1163 +++ 1164 +++ 1165+++ 1166 +++ 1167 +++ 1168 +++ 1169 +++ 1170 +++ 1171 +++ 1172 +++ 1173+++ 1173 +++ 1174 +++ 1175 +++ 1176 +++ 1177 +++ 1178 +++ 1179 +++ 1180+++ 1181 +++ 1182 +++ 1183 +++ 1184 +++ 1185 +++ 1186 +++ 1187 +++ 1188+++ 1189 +++ 1190 +++ 1191 +++ 1192 +++ 1193 +++ 1194 +++ 1195 +++ 1196+++ 1197 +++ 1198 +++ 1199 +++ 1200 +++ 1201 +++ 1202 +++ 1203 +++ 1204++ 1205 ++ 1206 +++ 1207 ++ 1208 +++ 1209 ++ 1210 +++ 1211 ++ 1212 +++1213 +++ 1214 +++ 1215 +++ 1216 +++ 1217 +++ 1218 +++ 1219 +++ 1220 +++1221 +++ 1222 +++ 1223 +++ 1224 ++ 1225 +++ 1226 +++ 1227 +++ 1228 +++1229 +++ 1230 +++ 1231 ND 1232 +++ 1233 ND 1234 +++ 1235 +++ 1236 +++1237 +++ 1238 +++ 1239 +++ 1240 +++ 1241 +++ 1242 +++ 1243 +++ 1244 +++1245 +++ 1246 ++ 1247 +++ 1248 ++ 1249 ++ 1250 ++

TABLE 4B Cmpd. IC₅₀ (μM)    1 0.281    2 3.10    3 4.72    4 3.52    57.64    6 7.39    7 12.0    8 >30.0    9 >30.0   10 6.51   11 6.85   122.39   13 1.07   14 >3.00   15 1.74   16 46.1   17 0.721   18 0.832   190.838   20 1.07   21 0.575   22 0.0249   23 0.624   24 0.184   25 12.6  26 0.919   27 0.149   28 0.0616   29 0.211   30 0.164   31 0.751   320.190   33 0.203   34 0.0885   35 0.0443   36 ND   37 0.0396   38 0.0555  39 0.116   40 0.540   41 3.44   42 19.8   43 >10.0   44 0.0731   452.89   46 0.0672   47 0.0224   48 0.631   49 >3.00   50 >3.00   510.0213   52 >3.00   53 0.931   54 2.28   55 0.0216   56 0.00789   570.0128   58 0.0502   59 0.0215   60 0.0147   61 0.0265   62 0.0249   630.0258   64 0.0625   65 0.0241   66 0.187   67 3.22   68 64.3   69 26.8  70 0.432   71 0.636   72 3.10   73 0.0832   74 0.423   75 1.40   762.30   77 1.44   78 1.63   79 1.65   80 0.110   81 4.22   82 1.66   832.56   84 1.25   85 1.85   86 49.7   87 1.16   88 1.68   89 >3.00   901.23   91 0.287   92 >3.00   93 1.40   94 1.42   95 2.86   96 2.10  97 >3.00   98 0.564   99 3.42  100 3.48  101 43.8  102 4.82  103 0.747 104 0.586  105 >3.00  106 1.38  107 3.82  108 11.2  109 19.2  110 26.9 111 0.434  112 >3.00  113 0.804  114 0.333  115 >3.00  116 >3.00 117 >3.00  118 0.416  119 0.0199  120 0.0357  121 0.0375  122 0.0244 123 0.0365  124 9.13  125 >3.00  126 8.36  127 0.0770  128 0.970  1293.10  130 1.42  131 0.600  132 0.624  133 0.0665  134 0.116  135 ND  1360.199  137 0.904  138 0.279  139 0.0346  140 0.0500  141 0.0442  1420.152  143 0.0167  144 0.132  145 0.0959  146 0.259  147 0.0147  1480.0205  149 0.110  150FA 0.0631  150FB 0.143  150FC 0.124  151 1.05 152 >3.00  153 0.0540  154 0.0972  155 0.0455  156 0.00420  157 ND  1580.0483  159 0.0309  160 0.00883  161 0.0904  162 0.0287  163 0.0955  1640.0164  165 0.106  166 0.0350  167 0.101  168 0.0372  169 0.234  1700.845  171 0.194  172 0.0923  173 0.141  174 0.0521  175 0.0204  1760.0415  177 0.0268  178 0.140  179 0.0206  180 0.0477  181 0.0623  1820.0438  183 0.0502  184 0.144  185 0.0949  186 0.344  187 0.0483  1880.0632  189 1.57  190 0.301  191 0.144  192 1.31  193 0.0209  194 0.0358 195 0.0274  196 0.0257  197 0.0524  198 0.124  199 0.143  200 0.0435 201 0.354  202 0.0474  203 0.0806  204 0.0444  205 0.101  206 0.229 207 0.0213  208 0.103  209 0.0470  210 0.0910  211 0.0354  212 0.0400 213 0.0356  214 0.0122  215 0.137  216 0.0628  217 0.0554  218 0.0169 219 0.109  220 0.213  221 0.113  222 0.0674  223 0.950  224 0.0110  2250.147  226 0.0707  227 0.507  228 0.0235  229 0.0222  230 0.0149  2310.0129  232 0.0163  233 0.0289  234 0.0185  235 0.0166  236 0.0203  2370.0548  238 0.0380  239 0.0286  240 0.00978  241 0.00487  242 0.0203 243 0.0432  244 0.0312  245 0.0256  246 0.0430  247 0.0611  248 0.0523 249 0.0198  250 0.0437  251 0.0311  252 0.0420  253 0.0460  254 0.0204 255 0.0785  256 0.104  257 0.0692  258 0.0377  259 >1.00  260 0.0204 261 0.0420  262 0.0224  263 0.0127  264 0.0246  265 0.0771  266 0.0266 267 0.0741  268 0.0341  269 0.0156  270 0.0464  271 0.0132  272 0.0229 273 0.0302  274 0.0188  275 0.0365  276 0.0228  277 0.0307  278 0.0127 279 0.0178  280 0.0412  281 0.0375  282 0.0171  283 0.0406  284 0.0196 285 0.0725  286 0.183  287 0.0478  288 0.0461  289 0.0191  290 0.0427 291 0.0995  292 0.203  293 0.0639  294 0.0229  295 0.167  296 0.0375 297 0.0363  298 0.101  299 0.0223  300 0.0243  301 0.0576  302 0.0776 303 0.498  304 1.60  305 0.431  306 0.0912  307 0.0594  308 0.811  3090.0525  310 0.0977  311 0.0555  312 0.0756  313 0.0345  314 0.0428  3150.582  316 0.0204  317 0.0171  318 0.00292  319 0.0535  320 0.0435  3210.00489  322 0.116  323 0.0826  324 0.0933  325 0.0520  326 1.44  3270.0437  328 1.32  329 0.0464  330 0.0477  331 ND  332 0.0377  333 0.0249 334 0.0104  335 0.0569  336 0.0279  337 0.0257  338 0.0453  339 0.0268 340 0.00501  341 0.0450  342 0.0474  343 0.0418  344 0.0321  345a0.0432  345b 0.0253  346 0.0181  347 0.0321  348 0.0154  349 0.00584 350 0.0142  351a 0.885  351b 0.0936  352 1.27  353 0.101  354 >1.00 355 0.146  356 1.22  357 0.0477  358 0.0863  359 0.0489  360 0.0426 361 0.0684  362 0.0722  363 0.0228  364 0.107  365 0.0190  366 0.00666 367 0.00287  368 0.0411  369 0.00132  370 0.0121  371 0.0200  3720.00734  373 0.00643  374 0.0205  375 0.0580  376 0.0127  377 0.0612 378 0.0451  379 0.0267  380 0.0297  381 ND  382 ND  383 ND  384 0.0209 385 0.0395  386 0.0254  387 0.619  388 0.00629  389 0.0123  390 0.00175 391 0.00352  392 0.0251  393 0.0118  394 0.0218  395 0.00968  3960.0181  397 0.0105  398 0.149  399 0.0699  400 0.00468  401 0.0474  4020.124  403 0.0126  404 0.0101  405 0.0197  406 0.0114  407 0.0331  4080.0311  409 0.0133  410 0.0626  411 0.193  412 0.0701  413 0.0346  4140.0205  415 0.0143  416 0.0230  417 0.0197  418 0.00907  419 0.00108 420 0.00960  421 0.0171  422 0.0115  423 0.00884  424 0.00408  4250.0112  426 0.0412  427 0.0250  428 0.00745  429 0.0382  430 0.00900 431 0.226  432 0.0258  433 0.00415  434 0.00776  435 0.0167  4360.00717  437 0.00621  438 0.00916  439a 0.00287  439b 0.0320  4400.00499  441 0.0204  442 0.0177  443 0.128  444 0.0308  445 0.0931  4460.0573  447 0.0848  448 0.00420  449 0.0196  450 0.00784  451 0.0360 452 0.0466  453 2.32  454 0.0511  455 0.473  456 0.0109  457 0.0112 458 0.0368  459 0.0415  460 0.0255  461 0.00615  462 0.0105  4630.00886  464 0.0214  465 0.0151  466 0.00930  467 0.0180  468 0.00436 469 0.00225  470 0.0128  471 0.0288  472 0.0236  473 0.0145  474 0.0135 475 0.0170  476 0.0339  477 0.00973  478 0.0132  479 0.0135  4800.00739  481 0.0105  482 0.0354  483 0.0421  484 0.0116  485 0.00859 486 0.0305  487 0.114  488 0.0265  489 0.0208  490 0.178  491 0.0229 492 0.0297  493 0.0942  494 0.0856  495 0.237  496 1.06  497 0.0397 498 0.0242  499 >1.00  500 0.0365  501 0.0257  502 0.0384  503 0.00867 504 0.0229  505 0.0436  506 0.0689  507 0.0490  508 0.0152  509 0.125 510 0.0505  511 0.0880  512 0.0718  513 0.0116  514 0.0399  515 0.0460 516 0.0344  517 0.0357  518 0.0164  519 0.0378  520 0.0183  521 0.623 522 0.0227  523 0.0239  524 0.0128  525 0.0347  526 0.0641  527 0.0248 528 0.0271  529 0.00578  530 0.00665  531 0.0429  532 0.0451  5330.0627  534 0.0302  535 0.244  536 0.0488  537 0.0466  538 0.0223  5390.0472  540 0.0140  541 0.0491  542 0.0202  543 0.0382  544 0.0282  5450.00781  546 0.0436  547 0.134  548 0.0472  549 0.0193  550 0.0878  5510.0292  552 0.0509  553 0.0134  554 0.0318  555 0.0108  556 0.0227  5570.00640  558 0.0272  559 0.00869  560 0.00477  561 0.0562  562 0.00878 563 0.0144  564 0.0405  565 0.0297  566 0.0164  567 0.0117  568 0.0141 569 0.00200  570 0.00557  571 0.0548  572 0.0306  573 0.0547  5740.0575  575 0.0257  576 0.0177  577 0.0394  578 0.0320  579 0.0302  5800.0242  581 0.00608  582 0.0127  583 0.0159  584 0.0235  585 0.0296  5860.0500  587 0.0255  588 0.0493  589 0.00445  590 0.00226  591 0.0449 592 0.0103  593 0.0329  594 1.35  595 0.0248  596 0.0377  597 0.0468 598 0.0572  599 0.0616  600 0.0142  601 0.0520  602 0.0102  603 0.0117 604 0.0707  605 ND  606 0.00412  607 0.00550  608 0.0186  609 0.0331 610 0.0139  611 0.00776  612 0.0438  613 0.00789  614 0.167  615 0.0163 616 0.00245  617 0.0397  618 0.00298  619 0.00634  620 0.0369  6210.0600  622 0.0438  623 0.00477  624 0.00402  625 0.0780  626 0.0104 627 0.00672  628 0.0285  629 0.00639  630 0.0502  631 0.00341  6320.0120  633 0.0129  634 0.00562  635 0.0106  636 0.0332  637 0.0166  6380.00446  639 0.00157  640 0.0240  641 0.0333  642 0.00363  643 0.000832 644 0.00497  645 0.0313  646 0.0414  647 0.0198  648 0.0246  649 0.0150 650 0.0283  651 0.0218  652 0.00668  653 0.0227  654 0.00312  6550.0135  656 0.0334  657 0.0457  658 1.29  659 0.0264  660 0.258  6610.0121  662 0.144  663 0.332  664 0.153  665 0.0165  666 0.268  6670.0467  668 0.00776  669 0.0364  670 0.0180  671 0.0777  672 0.106  6730.0253  674 0.00927  675 0.00777  676 0.00622  677 0.00544  678 0.0538 679 0.160  680 0.0566  681 0.0174  682 0.00621  683 0.0403  684 0.0150 685 0.0176  686 0.0265  687 0.0135  688 0.0228  689 0.0115  690 0.00595 691 0.00717  692 0.00597  693 0.0150  694 0.0191  695 0.00105  6960.00894  697 0.0102  698 0.00340  699 0.0121  700 0.0224  701 0.0192 702 0.0127  703 0.00318  704 0.0890  705 0.0191  706 0.140  707 0.0178 708 0.0878  709 0.0567  710 0.0316  711 0.0775  712 0.0196  713 0.0314 714 0.0472  715 ND  716 ND  717 0.0730  718 0.0201  719 0.0285  7200.199  721 0.0206  722 0.0380  723 0.0287  724 0.0377  725 0.0382  7260.0530  727 0.0294  728 0.0310  729 0.0925  730 0.0510  731 0.00597  7320.874  733 1.73  734 0.00468  735 0.0580  736 0.0170  737 0.0123  7380.0193  739 0.0308  740 0.0392  741 0.0152  742 0.0325  743 0.188  7440.0133  745 0.0333  746 0.0367  747 0.0189  748 0.0163  749 >100  7500.0415  751 0.0698  752 0.0276  753 0.0138  754 0.0172  755 0.0101  7560.0432  757 0.137  758 0.0131  759 0.0529  760 0.00644  761 0.0258  7620.0337  763 0.00519  764 0.0106  765 0.00919  766 0.0451  767 0.00751 768 0.0224  769 0.0239  770 0.0140  771 0.0128  772 0.0141  773 0.0102 774 0.00829  775 0.0483  776 0.0365  777 0.0533  778 0.0000702  7790.00954  780 0.00960  781 0.00312  782 0.00403  783 0.0148  784 0.0137 785 0.0182  786 0.0192  787 0.0109  788Fa 1.94  788Fb 0.00435  7890.00896  790 0.0178  791 0.00359  792 0.00244  793 0.00481  794 0.00341 795 0.0121  796 0.00327  797 0.00679  798 0.00986  799 0.00935  8000.0324  801 0.0170  802 0.0359  803 0.161  804 0.0188  805 0.0136  8060.00358  807 0.0210  808 0.0524  809 0.0160  810 0.00547  811 0.157  8120.0300  813 0.00404  814 ND  815 0.00331  816 0.00687  817 0.00724  8180.0131  819 0.0282  820 0.0136  821 0.0142  822 0.0107  823 0.0115  8240.0136  825 0.0143  826 0.0124  827 0.00572  828 0.00572  829 0.00453 830 0.0128  831 0.0123  832 ND  833 0.111  834 0.0316  835 0.0293  8360.00233  837 0.0134  838 0.0387  839 0.0296  840 0.0104  841 >1.00  8420.0209  843 0.0131  844 0.0233  845 0.0127  846 0.0379  847 0.0440  8480.0269  849 0.0145  850 0.0177  851 0.00602  852 0.0214  853 0.0319  8540.0119  855 0.00477  856 0.0137  857 0.00462  858 0.00728  859 0.00559 860 0.0103  861 0.0246  862 0.0209  863 0.0455  864 0.0479  865 0.0284 866 0.0168  867 0.00661  868 0.0172  869 0.0254  870 0.140  871 0.0164 872 0.0204  873 0.0157  874 0.0415  875 ND  876 0.0733  877 0.234  8780.00963  879 0.00731  880 0.0679  881 0.0204  882 0.00662  883 0.0128 884 0.00585  885 0.0307  886 0.0105  887 0.0201  888 0.0402  889 0.0124 890 0.0125  891 0.0137  892 0.0360  893 0.0201  894 0.0216  895 0.0229 896 0.00157  897 0.00140  898 0.0325  899 0.00744  900 0.0112  9010.0456  902 0.0142  903 0.0112  904 0.00419  905 0.00938  906 0.0176 907 0.00776  908 0.00326  909 0.0132  910 0.0175  911 0.0171  9120.00898  913 0.0162  914 0.0207  915 0.0184  916 0.00481  917 0.0110 918 0.00437  919 0.0177  920 0.00576  921 0.0696  922 0.0894  9230.00371  924 0.0143  925 0.0431  926 0.0183  927 0.00634  928 0.0387 929 0.0225  930 0.00688  931 0.0137  932 0.0178  933 0.122  934 0.0136 935 0.0196  936 ND  937 0.00136  938 0.00244  939 0.0121  940 0.470 941 0.0200  942 0.00693  943 0.0147  944 0.0462  945 0.0389  946 0.0277 947 0.0237  948 0.0183  949 0.0373  950 0.0172  951 0.0436  952 0.0450 953 0.0134  954 0.00829  955 0.0102  956 0.0165  957 0.00581  9580.0135  959 0.0148  960 0.0396  961 0.0211  962 0.00315  963 0.00784 964 0.00332  965 0.118  966 0.00358  967 0.0122  968 0.00895  9690.00556  970 0.166  971 0.0578  972 0.00977  973 0.0850  974 0.0236  9750.0148  976 0.0190  977 0.0144  978 0.0207  979 0.00948  980 0.0156  9810.0416  982 0.0204  983 0.0189  984 0.0115  985 0.00669  986 0.0169  9870.0136  988 0.0219  989 0.0198  990 0.0322  991 0.0121  992 0.0561  9930.0156  994 0.0234  995 0.0157  996 0.0316  997 0.0122  998 0.0451  9990.0163 1000 0.0167 1001 0.0312 1002 0.00237 1003 0.0134 1004 0.0225 10050.0334 1006 0.0182 1007 0.0482 1008 0.0153 1009 0.00623 1010 0.005291011 0.00715 1012 0.00894 1013 0.0185 1014 0.0256 1015 0.0197 10160.00111 1017 0.00826 1018 0.00671 1019 0.0308 1020 0.0234 1021 0.02111022 0.0424 1023 0.0498 1024 0.0242 1025 0.0300 1026 0.0155 1027 0.03151028 0.00614 1029 0.00766 1030 0.0144 1031 0.0116 1032 0.00620 10330.0200 1034 0.0379 1035 0.0197 1036 0.00351 1037 0.0119 1038 0.0389 10390.0217 1040 0.0300 1041 0.00621 1042 0.0265 1043 0.00398 1044 0.005311045 0.0382 1046 0.0380 1047 0.0212 1048 0.0137 1049 0.00935 1050 0.01951051 0.00502 1052 0.00546 1053 0.00508 1054 0.0186 1055 0.0117 10560.0161 1057 0.0125 1058 0.0397 1059 0.0111 1060 0.0509 1061 0.00854 10620.00663 1063 0.0312 1064 0.0162 1065 0.0186 1066 0.0574 1067 0.0105 10680.0278 1069 0.00152 1070 0.0320 1071 0.0540 1072 0.0372 1073 0.0581 10740.0174 1075 0.00664 1076 0.0245 1077 0.245 1078 0.347 1079 0.0559 10800.105 1081 1.04 1082 0.903 1083 0.0440 1084 0.0150 1085 0.0543 10860.0384 1087 0.0392 1088 0.0533 1089 0.618 1090a 0.0383 1090b 0.503 10910.0914 1092 0.0427 1093 0.0586 1094 0.0716 1095 0.0465 1096 0.0335 10970.0388 1098 0.0156 1099 0.0375 1100 0.0335 1101 0.00720 1102 0.0192 11030.0148 1104 0.631 1105 0.0217 1106 0.0174 1107 0.0105 1108 0.0291 11090.0134 1110 0.00720 1111 0.00571 1112 0.0199 1113 0.140 1114 0.0499 11150.00677 1116 0.0171 1117 0.0134 1118 0.0140 1119 0.0146 1120 0.009511121 0.00926 1122 0.0146 1123 0.0215 1124 0.0132 1125 0.0145 1126 0.02661127 0.0129 1128 0.0239 1129 0.0107 1130 0.00439 1131 0.0147 1132 0.01331133 0.0170 1134 0.0153 1135 0.0343 1136 0.0170 1137 0.0174 1138 0.02371139 ND 1140 0.00614 1141 0.0189 1142 0.0130 1143 0.0246 1144 0.03441145 0.0331 1146 0.0144 1147 0.0446 1148 0.0356 1149 0.00419 11500.00460 1151 0.0190 1152 0.00380 1153 0.0380 1154 0.0140 1155 0.01811156 0.0351 1157 0.0220 1158 0.0158 1159 0.0147 1160 0.0172 1161 0.01951162 0.0216 1163 0.0248 1164 0.0267 1165 0.0223 1166 0.0286 1167 0.01731168 0.0130 1169 0.0153 1170 0.0171 1171 0.0130 1172 0.0142 1173a 0.01921173b 0.0130 1174 0.00932 1175 0.0221 1176 0.0343 1177 0.0342 11780.0229 1179 0.0147 1180 0.0162 1181 0.0137 1182 0.0136 1183 0.0232 11840.00932 1185 0.0176 1186 0.0201 1187 0.0186 1188 0.0124 1189 0.0134 11900.00730 1191 0.0128 1192 0.0488 1193 0.0102 1194 0.0153 1195 0.0131 11960.0306 1197 0.00593 1198 0.0130 1199 0.0182 1200 0.0148 1201 0.0228 12020.0197 1203 0.00915 1204 0.150 1205 0.199 1206 0.0325 1207 0.121 12080.0489 1209 0.0980 1210 0.0483 1211 >1.00 1212 0.0442 1213 0.0427 12140.00508 1215 0.0257 1216 0.0103 1217 0.0242 1218 0.0131 1219 0.003991220 0.0131 1221 0.0300 1222 0.00302 1223 0.00279 1224 0.0760 12250.00312 1226 0.00663 1227 0.0128 1228 0.00111 1229 0.0107 1230 0.01031231 ND 1232 0.00449 1233 ND 1234 0.0302 1235 0.00632 1236 0.0339 12370.00668 1238 0.0130 1239 0.0182 1240 0.0155 1241 0.0173 1242 0.008851243 0.00555 1244 0.0194 1245 0.0156 1246 0.106 1247 0.0355 1248 0.06071249 0.0759 1250 0.0758 1251 0.00477 1252 0.222 1253 0.00840 1254 0.02651255 0.150 1256 0.0247 1257 0.0525 1258 0.0615 1259 0.00538 1260 0.01301261 0.0336 1262 0.0106 1263 0.0106 1264 0.0124 1265 0.0115 1266 0.009071267 >1.00 1268 0.472 1269 0.0666 1270 0.0399 1271 0.0131 1272 0.02811273 0.00748 1274 0.0402 1275 0.0587 1276 0.0135 1277 0.0384 1278 0.01061279 0.00891 1280 0.00426 1281 0.117 1282 0.0382 1283 0.0335 1284 >1.001285 0.0413 1286 0.0342 1287 0.0424 1288 0.0367 1289 0.0140 1290 0.1491291 0.0412 1292 0.0523 1293 0.0351 1294 0.0559 1295 0.0134 1296 0.02701297 0.0378 1298 0.0383 1299 0.0321 1300 0.0181 1301 0.0155 1302 0.03071303 0.0366 1304 0.0185 1305 0.0265 1306 0.0389 1307 0.0542 1308 0.04151309 0.0372 1310 0.0213 1311 0.0133 1312 0.00829 1313 0.0426 1314 0.01811315 0.0131 1316 0.0328 1317 0.0335 1318 0.0344 1319 0.0136 1320 0.02771321 0.0602 1322 0.0112 1323 0.0730 1324 0.0237 1325 0.0271 1326 0.01281327 0.0193 1328 0.0248 1329 0.0352 1330 0.0130 1331 0.0918 1332 0.03451333 0.0262 1334 0.0513 1335 0.0128 1336 0.0130 1337 0.0519 1338 0.009501339 0.0364 1340 0.0442 1341 0.0215 1342 0.0304 1343 0.0406 1344 0.01831345 0.0345 1346 0.0197 1347 0.0414 1348 0.0122 1349 0.0365 1350 0.03511351 0.0160 1352 0.0216 1353 0.0172 1354 0.0216 1355 0.0248 1356 0.02321357 0.0159 1358 0.0183 1359 0.0397 1360 0.0168 1361 0.0213 1362 0.01411363 0.0429 1364 0.0247 1365 0.0341 1366 0.0143 1367 0.0149 1368 0.01991369 0.0132 1370 0.0199 1371 0.0151 1372 0.0807 1373 0.0267 1374 0.05611375 0.0839 1376 0.0136 1377 0.0440 1378 0.0300 1379 0.0180 1380 0.02661381 0.00796 1382 0.0216 1383 0.00503 1384 0.00686 1385 0.00724 13860.0128 1387 0.0228 1388 0.0362 1389 1.19 1390 ND 1391 0.0376 1392 0.02651393 0.0132 1394 0.00474 1395 0.0296 1396 0.0195 1397 0.0147 1398 0.01401399 0.0144 1400 0.0278 1401 0.0127 1402 0.00658 1403 0.00876 1404 0.4821405 0.631 1406 0.0266 1407 0.0247 1408 0.0176 1409 0.0108 1410 0.01801411 0.0175 1412 0.00671 1413 0.0517 1414 0.0153 1415 0.0168 1416 0.01271417 0.0249 1418 0.00910 1419 0.00676 1420 0.00633 1421 0.0366 14220.0335 1423 0.0232 1424 0.0292 1425 0.0130 1426 0.0117 1427 0.0143 14280.0122 1429 0.0178 1430 0.0228 1431 0.0198 1432 0.0212 1433 0.0274 14340.0290 1435 0.0264 1436 0.0295 1437 0.0373 1438 0.0408 1439 0.0128 14400.0690 1441 0.0298 1443 0.0316 1444 0.0252 1445 0.0320 1446 0.0140 14470.0316 1448 0.0260 1449 0.0170 1450 0.0134 1451 0.0217 1452 0.0391 14530.0146 1454 0.00615 1455 0.0211 1456 0.0184 1457 0.0180 1458 0.0191 14590.0207 1460 0.00799 1461 0.0138 1462 0.0201 1463 0.0229 1464 0.0134 14650.0236 1466 0.0179 1467 0.0110 1468 0.0350 1469 0.0230 1470 0.0308 14710.0142 1472 0.0289 1473 0.0169 1474 0.0138 1475 0.00720 1476 0.0162 14770.0181 1478 0.0130 1479 0.0167 1480 ND 1481 0.0208 1482 0.0166 14830.0137 1484 0.0229 1485 0.0229 1486 0.0107 1487 0.0254 1488 0.0123 14890.0137 1490 0.0291 1491 0.0290 1492 0.0201 1493 0.00683 1494 0.0247 14950.00709 1496 0.0325 1497 0.0129 1498 0.0291 1499 0.0275 1500 0.0170 15010.0205 1502 0.0262 1503 0.0192 1504 0.0136 1505 0.0130 1506 0.0274 15070.0160 1508 0.0174 1509 0.0375 1510 0.0201 1511 0.0232 1512 0.0122 15130.0134 1514 0.0517 1515 0.0321 1516 0.0170 1518 0.0107 1519 0.0153 15200.0179 1521 0.0183 1522 0.0177 1523 0.0131 1524 0.0125 1525 0.0151 15260.0112 1527 0.0156 1528 0.00631 1529 0.0201 1530 0.0335 1531 0.0134 15320.0112 1533 0.0217 1534 0.0158 1535 0.0174 1536 0.0183 1537 0.0189 15380.0145 1539 0.0125 1540 0.0195 1541 0.0106 1542 0.0186 1543 0.0205 15440.0131 1545 0.0275 1546 0.0134 1547 0.0152 1548 0.0362 1549 0.0262 15500.0229 1551 0.0220 1553 0.0129 1554 0.0151 1555 0.0239 1556 0.0499 15570.00677 1558 0.0690 1559 0.0134 1560 0.00631 1561 0.0130 1562 0.01681563 0.0130 1564 0.0106 1565 0.00799 1566 0.00439 1568 0.0216 15690.0195 1570 0.0229 1571 0.0205 1572 0.0200 1573 0.0222 1574 0.0134 15750.0147 1576 0.0179 1577 0.0133 1578 0.0203 1579 0.0303 1581 0.0143 15820.0192 1583 0.0582 1584 0.0369 1585 0.0152 1586 0.0318 1587 0.0397 15880.0264 1589 0.0124 1590 0.0360 1591 0.0362 1592 0.0203 1593 0.0616 15940.442 1595 0.0548 1596 0.654 1597 0.0221 1598 0.0375 1599 0.0167 16000.0203 1601 0.00805 1602 0.00388 1603 0.00212 1604 0.00396 1605 0.003781606 0.00460 1607 0.0146 1608 0.00659 1609 0.00488 1610 0.00602 16110.00385 1612 0.0137 1613 0.0161 1614 0.0314 1615 0.0147 1616 0.0115 16170.0156 1618 0.0124 1619 0.0316 1620 0.0179 1621 0.0721 1622 0.0173 1623ND 1624 0.00417 1625 ND 1626 0.0303 1627 ND 1628 ND 1629 ND 1630 ND 16310.0161 1632 0.0424 1633 0.0526 1634 0.0174 1635 0.0215 1636 0.0388 16370.0177 1638 0.0388 1639 0.0305 1640 ND 1641 0.0189 1642 0.0245 16430.0188 1644 0.0145 1645 0.0232 1646 0.0263 1647 0.0196 1648 0.0133 16490.0183 1650 0.0107 1651 ND 1652 ND 1653 0.0265 1654 0.0210 1655 0.01341656 ND 1657 ND 1658 ND 1659 ND 1660 ND 1661 ND 1662 0.0221 1663 0.01411664 ND 1665 0.0146 1666 ND 1667 0.0122 1668 0.00567 1669 0.00917 16700.00568 1671 0.00414 1672 0.0132 1673 0.00722 1674 0.00650 1675 0.004111676 0.00433 1677 0.0129 1678 0.0280 1679 0.0293 1680 0.0233 16810.00827 1682 0.0151 1683 0.0183 1684 ND 1685 ND 1686 ND 1687 ND 16880.0127 1689 0.0222 1690 0.0274 1691 0.0179 1692 ND 1693 ND 1694 ND 1695ND 1696 ND 1697 ND 1698 ND 1699 ND 1700 ND 1701 ND 1702 ND 1703 0.006001704 0.00654 1705 0.00480 1706 0.0121 1707 0.0157 1708 0.0162 17090.0284 1710 ND 1711 ND 1712 ND 1713 0.0158 1714 ND 1715 ND 1716 ND 17170.0134 1718 ND 1719 ND 1720 ND 1721 ND 1722 ND 1723 ND 1724 0.00407 1725ND 1726 ND 1727 0.00384 1728 ND 1729 ND 1730 ND 1731 ND 1732 ND 17330.00811 1734 0.0194 1735 0.0336 1736 0.0126 1737 0.0143 1738 0.0255 17390.0333 1740 0.0126 1741 0.0110 1742 0.00543 1743 0.00687 1744 0.01151745 0.0110 1746 0.0108 1747 0.0165 1748 0.0175 1749 0.0164 1750 0.01611751 ND 1752 ND 1753 ND 1754 ND 1755 ND 1756 ND 1757 ND 1758 ND 1759 ND1760 ND 1761 0.00565 1762 0.0250 1763 0.0233 1764 0.0190 1765 0.01231766 ND 1767 0.0174 1768 0.0313 1769 0.0164 1770 0.0175 1771 0.0266 17720.00607 1773 0.0475 1774 0.0450 1775 0.0321 1776 0.00365 1777 ND 1778 ND1779 0.0351 1780 0.0109 1781 0.00832 1782 ND 1783 ND 1784 ND 1785 ND1786 ND 1787 ND 1788 ND 1789 ND 1790 ND 1791 0.0101 1792 0.00924 17930.00729 1794 0.00928 1795 0.00896 1796 ND 1797 ND 1798 ND 1799 ND 1800ND 1801 ND 1802 ND 1803 ND 1804 ND 1805 ND 1806 ND 1807 0.0104 18080.00540 1809 0.00757 1810 0.0129 1811 0.0127 1812 0.0184 1813 ND 1814 ND1815 ND 1816 ND 1817 0.0258 1818 0.0130 1819 0.00440 1820 0.0122 1821 ND1822 ND 1823 ND 1824 ND 1825 0.0171 1826 0.0184 1827 0.0148 1828 ND 18290.00627 1830 0.00806 1831 0.00500 1832 0.0205 1833 0.0148 1834 ND 1835ND 1836 ND 1837 ND 1838 0.0123 1839 0.0345 1840 0.0264 1841 ND 1842 ND1843 ND 1844 ND 1845 ND 1846 ND 1847 ND 1848 ND 1849 ND 1850 ND 1851 ND1852 ND 1853 ND 1854 ND 1855 ND 1856 ND 1857 ND 1858 ND 1859 ND 1860 ND1861 ND 1862 ND 1863 ND 1864 ND 1865 ND 1866 ND 1867 ND 1868 ND 1869 ND1870 ND 1871 ND 1872 ND 1873 ND 1874 ND 1875 ND 1876 ND 1877 ND 1878 ND1879 ND 1880 ND 1881 ND 1882 ND 1883 ND 1884 ND 1885 ND 1886 ND 1887 ND1888 ND 1889 ND 1890 ND 1891 ND 1892 ND 1893 ND 1894 ND 1895 0.0127 18960.0122 1897 0.0131 1898 0.0613 1899 0.0164 1900 2.70 1901 0.0357 19020.0842 1903 0.0298 1904 0.0369 1905 0.881 1906 ND 1907 0.405 19080.00517 1909 0.0292 1910 0.0474 1911 0.00403 1912 0.00596 1913 0.02291914 ND 1915 ND 1916 ND 1917 ND 1918 ND 1919 ND 1920 ND 1921 ND 1922 ND1923 ND 1924 ND 1925 ND 1926 ND 1927 ND 1928 ND 1929 ND 1930 0.004811931 0.0197 1932 0.00840 1933 0.0346 1934 0.0385 1935 0.0801 1936 0.03741937 0.0382 1938 0.0463 1939 0.0245 1940 0.0349 1941 0.0616 1942 0.1821943 0.0424 1944 0.0249 1945 0.0449 1946 0.0447 1947 0.0297 1948 0.03561949 0.0216 1950 0.0417 1951 0.0199 1952 ND 1953 0.0893 1954 0.0170 1955ND 1956 ND 1957 ND 1958 ND 1959 0.0463 1960 43.2 1961 0.211 1962 ND 19630.241 1964 0.0498 1965 0.0864 1966 ND 1967 ND 1968 ND 1969 ND 19700.0672 1971 0.0519 1972 0.0180 1973 0.0143 1974 0.0513 1975 0.109 19761.85 1977 >1.00 1978 0.0253 1979 ND 1980 ND 1981 0.0238 1982 0.0364 19830.0826 1984 ND 1985 ND 1986 0.0785 1987 1.29 1988 0.0495 1989 0.08901990 0.0581 1991 >300 1992 0.490 1993 0.412 1994 0.0418 1995 0.0593 19960.189 1997 0.0775 1998 0.409 1999 0.482 2000 18.2 2001 65.8 2002 0.2592003 0.264 2004 0.639 2005 0.364 2006 0.611 2007 >300 2008 0.0961 20092.15 2010 1.19 2011 0.529 2012 ND 2013 >10.0 2014 12.2 2015 0.0511 20160.613 2017 0.0506 2018 0.0244 2019 0.0249 2020 0.0330 2021 ND 2022 ND2023 ND 2024 ND 2025 ND 2026 0.656 2027 >1.00 2028 >1.00 2029 ND 2030 ND2031 ND 2032 ND 2034 0.00620 2035 0.0723 2036 0.0384 2037 >1.00 2038 ND2039 ND 2041 ND 2042 ND

Example 5B. Cell Proliferation Assays

MDA-MB-361 cells were maintained in DMEM supplemented with 10% FBS and1× penicillin/streptomycin solution at 37° C. in a CO₂ incubator. Forcell proliferation assays, exponentially growing cells were seeded at2,000 cells per well in 96-well flat bottom white polystyrene plates(ThermoFisher) and cultured overnight. The following day, compound wasadded in a 9 point 3-fold dilution series starting from a topconcentration of 1 or 10 μM (as indicated) together with a DMSO control.The final DMSO concentration in samples was 0.1%.

Cells were incubated for up to 6 days hours at 37° C. in a CO₂incubator. Baseline viability of untreated cells was measured on the dayof treatment and proliferation was measured after 6 days hours oftreatment using CELLTITER-GLO® reagent from Promega (Madison, Wis.)according to the manufacturer's instructions. Response to compound wascalculated relative to the DMSO control (% of control) using theformula, % of control(DMSO)=[(CTG_(cells)+inhibitor)/(CTG_(DMSO control))]×100. Data wereplotted using Prism (GraphPad software), and IC₅₀ and E_(max) valueswere calculated from a 4 parameter, variable slope non-linear regressionmodel. Results are shown below and in FIGS. 1-3 .

Compound Mean IC50 (nM) n 1188 46.8* 7 634 3.8 3 1141 361 2 *95% CI (nM)35.1-62.2, E_(max) (%), 90.2

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

1-29. (canceled)
 30. A method of treating an eIF4E dependent conditionin a subject comprising: administering to the subject a compound ofFormula III:

wherein: L¹ is —(CH₂)—, —(CH₂)₂—, —(CH₂)₃—, —CH((C₁-C₈)alkyl)(CH₂)—,—CH((C₁-C₈)alkyl)(CH₂)₂—, —(CH₂)₂—O—, —CH₂CH═CH—, —CH₂C≡C— or—CH₂(cyclopropyl)-; L² is —C(R⁶)(R⁶)—, —C(R⁶)(R⁶)C(R⁶)(R⁶)—,—C(R⁶)═C(R⁶)—, —N(R⁵)C(R⁶)(R⁶)—, —OC(R⁶)(R⁶)—, —C(═O)—,—C(═O)N(R⁵)C(R⁶)(R⁶)— or a bond; Ring C is a heteroaryl; R¹ is H, OH,halo, CN, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₃-C₆)cycloalkyl or NR⁵R⁵; R²is independently H, halo, CN, NO, NO₂, C≡CH, (C₁-C₈)alkyl,(C₁-C₈)haloalkyl, CH₂SR⁵, OR⁵, NHR⁵, NR⁵R⁵,[(C₁-C₈)alkylene]heterocyclyl, [(C₁-C₈)alkylene]heteroaryl,[(C₁-C₈)alkylene]NHR⁵, [(C₁-C₈)alkylene]NR⁵R⁵, C(O)R⁵, C(O)OR⁵,C(O)NHR⁵, C(O)NR⁵R⁵, SR⁵, S(O)R⁵, SO₂R⁵, SO₂NHR⁵, SO₂NR⁵R⁵, NH(CO)R⁶,NR⁵(CO)R⁶, aryl, heteroaryl, cycloalkyl or heterocyclyl; R³ isindependently OH, halo, CN, NO₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₁-C₆)alkoxy, C≡CH, NHR⁷, NR⁷R⁷, CO₂H, CO₂R⁷, [(C₁-C₃)alkylene](C₁-C₃)alkoxy, [(C₁-C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, ═O. ═S, SR⁷,SO₂R⁷, NH(CO)R⁷ or NR⁷(CO)R⁷; R⁵ is independently H, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, (C₃-C₅)cycloalkyl or heterocyclyl; R⁶ is independentlyH, OH, halo, CN, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkoxy, NHR⁷,NR⁷R⁷, CO₂H, [(C₁-C₃)alkylene]CO₂H, (C₃-C₅)cycloalkyl, SR⁷, NH(CO)R⁷ orNR⁷(CO)R⁷; R⁷ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl; R⁸ is H, OH, CO₂H, CO₂R⁷,CF₂C(R⁶)₂OH, C(R⁶)₂OH, C(CF₃)₂OH, SO₂H, SO₃H, CF₂SO₂C(R⁶)₃,CF₂SO₂N(H)R⁵, SO₂N(H)R⁵, SO₂N(H)C(O)R⁶, C(O)N(H)SO₂R⁵, C(O)haloalkyl,C(O)N(H)OR⁵, C(O)N(R⁵)OH, C(O)N(H)R⁵, C(O)NR⁵C(O)N(R⁵)₂, P(O)(OR⁵)OH,P(O)(C(R⁶)₃)C(R⁶)₃, B(OH)₂, heterocyclyl or heteroaryl; R⁹ is H,(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl or heterocyclyl; m is 0, 1,or 2; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3; wherein any alkyl, alkylene,cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substitutedwith 1, 2 or 3 groups selected from OH, CN, SH, SCH₃, SO₂CH₃, SO₂NH₂,SO₂NH(C₁-C₄)alkyl, halogen, NH₂, NH(C₁-C₄)alkyl, N[(C₁-C₄)alkyl]₂,NH(aryl), C(O)NH₂, C(O)NH(alkyl), CH₂C(O)NH(alkyl), COOH, COOMe, acetyl,(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, thioalkyl, cyanomethylene, alkylaminyl,alkylene-C(O)NH₂, alkylene-C(O)—NH(Me), NHC(O)alkyl,CH₂—C(O)—(C₁-C₈)alkyl, C(O)—(C₁-C₈)alkyl, and alkylcarbonylaminyl, andone or more other therapeutic agents.
 31. The method of claim 30,wherein L² is a bond.
 32. The method of claim 30, wherein Ring C is


33. The method of claim 30, wherein the compound of Formula (III) isselected from the group consisting of


34. The method of claim 30, wherein the eIF4E dependent condition isselected from the group consisting of cell proliferative disorders,inflammatory diseases, and fibrotic diseases.
 35. The method of claim34, wherein the cell proliferative disorder is cancer, wherein thecancer is colon cancer, gastric cancer, thyroid cancer, lung cancer,leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma,pancreatic cancer, melanoma, brain cancer, CNS cancer, renal cancer,prostate cancer, ovarian cancer, or breast cancer.
 36. The method ofclaim 35, wherein the cancer is breast cancer, prostate cancer, or lungcancer.
 37. The method of claim 35, wherein the cancer is a metastaticcancer.
 38. The method of claim 35, wherein the other therapeutic agentis an anti-cancer agent.
 39. The method of claim 38, wherein thecompound of formula (III) is selected from the group consisting of


40. The method of claim 38, wherein the anticancer agent is achemotherapeutic agent, radiation, or an immune checkpoint molecule. 41.The method of claim 39, wherein the chemotherapeutic agent is selectedfrom the group consisting of pyrimidine analogs, purine analogs, folateantagonists, antiproliferative agents, antimitotic agents, microtubuledisruptors, DNA damaging agents, antibiotics, enzymes, antiplateletagents, antiproliferative agents, antimitotic alkylating agents,platinum coordination complexes, hormones, hormone analogs, aromataseinhibitors, anticoagulants, fibrinolytic agents, antimigratory agents,antisecretory agents, immunosuppressives, anti-angiogenic compounds,growth factor inhibitors, angiotensin receptor blocker, nitric oxidedonors, anti-sense oligonucleotides, antibodies, chimeric antigenreceptors, cell cycle inhibitors, differentiation inducers, mTORinhibitors, topoisomerase inhibitors, corticosteroids, growth factorsignal transduction kinase inhibitors, mitochondrial dysfunctioninducers, caspase activators, chromatin disruptors, and toxins.
 42. Themethod of claim 40, wherein the compound of formula (III) is

and the chemotherapeutic agent is selected from the group consisting of:5-fluorouracil, floxuridine, capecitabine, gemcitabine, mercaptopurine,thioguanine, pentostatin, 2-chlorodeoxyadenosine, vinblastine,vincristine, and vinorelbine, taxane, vincristin, vinblastin,nocodazole, epothilones, navelbine, etoposide, teniposide, actinomycin,amsacrine, anthracyclines, bleomycin, busulfan, camptothecin,carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan,dactinomycin, daunorubicin, doxorubicin, epirubicin,hexamethylmelamineoxaliplatin, iphosphamide, melphalan,merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin,procarbazine, taxol, taxotere, temozolamide, teniposide,triethylenethiophosphoramide, etoposide, dactinomycin, daunorubicin,doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycins,plicamycin, mitomycin, L-asparaginase, mechlorethamine,cyclophosphamide, melphalan, chlorambucil, hexamethylmelamine, thiotepa,carmustine, streptozocin, trazenes-dacarbazinine, methotrexate,cisplatin, carboplatin, procarbazine, hydroxyurea, mitotane,aminoglutethimide, estrogen, tamoxifen, goserelin, bicalutamide,nilutamide, letrozole, anastrozole, heparin, streptokinase, urokinase,aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab, breveldin,cyclosporine, tacrolimus, sirolimus, azathioprine, mycophenolatemofetil, TNP470, genistein, trastuzumab, rituximab, tretinoin,doxorubicin, amsacrine, camptothecin, daunorubicin, dactinomycin,eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone,topotecan, irinotecan, cortisone, dexamethasone, hydrocortisone,methylpednisolone, prednisone, prednisolone, Cholera toxin, ricin,Pseudomonas exotoxin, Bordetellapertussis adenylate cyclase toxin, anddiphtheria toxin.
 43. The method of claim 38, wherein the compound offormula (III) is administered concurrently with the anticancer agent.44. The method of claim 38, wherein the compound of formula (III) isadministered at separately staggered times from the anticancer agent.45. The method of claim 40, wherein the immune checkpoint molecule isselected from the group consisting of PD-L1, PD-L2, CD80, CD86, B7-H3,B7-H4, HVEM, adenosine, GAL9, VISTA, CEACAM-1, CEACAM-3, CEACAM-5,PVRL2, PD-1, CTLA-4, BTLA, KIR, LAG3, TIM3, A2aR, CD244/2B4, CD160,TIGIT, LAIR-1, PVRIG/CD112R, arginase, indoleamine 2,3-dioxygenase,IL-10, IL-4, IL-1RA, and IL-35.
 46. The method of claim 34, wherein thefibrotic disease is selected from the group consisting of viralhepatitis, hepatic fibrosis, schistosomiasis, steatohepatitis,cirrhosis, idiopathic pulmonary fibrosis, systemic sclerosis,nephrogenic systemic fibrosis, diabetes, untreated hypertension, heartattack, hypertension, atherosclerosis, restenosis, macular degeneration,retinal and vitreal retinopathy, keloids, hypertrophic scars, Crohn'sdisease and Alzheimer's disease.
 47. The method of claim 34, wherein theinflammatory disease is selected from the group consisting of chronicinflammation, acute inflammation, chronic inflammatory arthritis,rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenilerheumatoid arthritis, Reiter's syndrome, rheumatoid traumatic arthritis,rubella arthritis, acute synovitis, gouty arthritis; inflammatory skindiseases, sunburn, psoriasis, erythrodermic psoriasis, pustularpsoriasis, eczema, dermatitis, acute graft formation, chronic graftformation, atopic dermatitis, contact dermatitis, urticaria scleroderma,inflammatory bowel disease, Crohn's disease, ulcerative colitis,colitis, diverticulitis, nephritis, urethritis, salpingitis, oophoritis,endomyometritis, spondylitis, systemic lupus erythematosus, multiplesclerosis, asthma, meningitis, myelitis, encephalomyelitis,encephalitis, phlebitis, thrombophlebitis, asthma, bronchitis, chronicobstructive pulmonary disease, inflammatory lung disease, adultrespiratory distress syndrome, allergic rhinitis, endocarditis,osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumaticendocarditis, rheumatic myocarditis, rheumatic mitral valve disease,rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis,bursitis, gout, pseudo gout, vasculitides, granulomatous thyroiditis,lymphocytic thyroiditis, invasive fibrous thyroiditis, acutethyroiditis; Hashimoto's thyroiditis, Kawasaki's disease, Raynaud'sphenomenon, Sjögren's syndrome, neuroinflammatory disease, sepsis,conjunctivitis, keratitis, iridocyclitis, optic neuritis, otitis,lymphoadenitis, nasopaharingitis, sinusitis, pharyngitis, tonsillitis,laryngitis, epiglottitis, bronchitis, pneumonitis, stomatitis,gingivitis. oesophagitis, gastritis, peritonitis, hepatitis,cholelithiasis, cholecystitis, glomerulonephritis, Goodpasture'sdisease, crescentic glomerulonephritis, pancreatitis, endomyometritis,myometritis, metritis, cervicitis, endocervicitis, exocervicitis,parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.
 48. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 49. A compound having theformula: